Substituted piperidinamines as somatostatin receptor subtype 5 (SSTR5) antagonists

ABSTRACT

This invention is concerned with compounds of the formula 
                         
and pharmaceutically acceptable salts thereof. The invention further relates to pharmaceutical compositions containing such compounds, to a process for their preparation and to their use for the treatment and/or prevention of diseases which are associated with the modulation of SST receptors subtype 5.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of European Patent Application No.06118923.9, filed Aug. 15, 2006, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention is concerned with novel phenyl, pyridine,quinoline, isoquinoline, naphthyridine and pyrazine derivatives, theirmanufacture, pharmaceutical compositions containing them and their useas medicaments. The active compounds of the present invention are usefulin the prevention and/or treatment of diabetes mellitus and otherdisorders.

In particular, the present invention is concerned with compounds of thegeneral formula I

and pharmaceutically acceptable salts thereof.

The compounds of formula I possess pharmaceutical activity, inparticular they are modulators of somatostatine receptor activity. Moreparticularly, the compounds are antagonists of the somatostatinereceptor subtype 5 (SSTR5).

All documents cited or relied upon below are expressly incorporatedherein by reference.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a systemic disease characterized by metabolicdisorders involving insulin, carbohydrates, fats and proteins, anddisorders in the structure and function of blood vessels. The primarysymptom of acute diabetes is hyperglycemia, often accompanied byglucosuria, the presence in urine of large amounts of glucose, andpolyuria, the excretion of large volumes of urine. Additional symptomsarise in chronic diabetes, including degeneration of the walls of bloodvessels. Although many different human organs are affected by thesevascular changes, the eyes and kidneys appear to be the mostsusceptible. As such, long-standing diabetes mellitus, even when treatedwith insulin, is a leading cause of blindness.

There are three recognized types of diabetes mellitus. Type I diabetesor insulin dependent diabetes mellitus (IDDM) is typically of juvenileonset; ketosis develops early in life with much more severe symptoms andhas a near-certain prospect of later vascular involvement. Control ofType I diabetes is difficult and requires exogenous insulinadministration. Type II diabetes or non-insulin dependent diabetesmellitus (NIDDM) is ketosis-resistant, generally develops later in life,is milder and has a more gradual onset. Gestational diabetes is relatedto type II diabetes and associated with an increased risk of laterdevelopment of that disease. Type III diabetes is malnutrition-relateddiabetes.

NIDDM is a condition that poses a major threat to the health of thecitizens of the western world. NIDDM accounts for over 85% of diabetesincidence worldwide and about 160 million people are suffering fromNIDDM. The incidence is expected to increase considerably within thenext decades, especially in developing countries. NIDDM is associatedwith morbidity and premature mortality resulting from seriouscomplications, e.g., cardiovascular disease (G. C. Weir and J. L. Leahy,Pathogenesis of non-insulin dependent (Type II) diabetes mellitus, inJoslin's Diabetes Mellitus (Eds. C. R. Kahn and G. C. Weir), 13^(th)Edition, 1994, Lea & Febiger, Malvern, Pa., pp. 240-264). NIDDM ischaracterized by both fasting and post-prandial hyperglycemia resultingfrom abnormalities in insulin secretion and insulin action (G. C. Weiret al., vide supra).

The hyperglycemia in patients suffering from NIDDM can usually beinitially treated by dieting, but eventually most NIDDM patients have totake oral antidiabetic agents and/or insulin injections to normalizetheir blood glucose levels. The introduction of orally effectivehypoglycemic agents was an important development in the treatment ofhyperglycemia by lowering blood glucose levels. Currently, the mostwidely used oral antidiabetic agents are the sulfonylureas, which act byincreasing the secretion of insulin from the pancreas (H. E. Lebovitz,Oral antidiabetic agents, in Joslin's Diabetes Mellitus (Eds. C. R. Kahnand G. C. Weir), 13^(th) Edition, 1994, Lea & Febiger, Malvern, Pa., pp.508-529), the biguanides (e.g., metformin) which act on the liver andperiphery by unknown mechanisms (C. J. Bailey, M. R. C. Path and R. C.Turner N. Engl. J. Med. 1996, 334, 574-579) and the thiazolidinediones(e.g., rosiglitazone/Avandia®), which enhance the effects of insulin atperipheral target sites (G. L. Plosker and D. Faulds Drugs 1999, 57,409-438). These existing therapies which comprise a wide variety ofbiguanide, sulfonylurea and thiazolidinedione derivatives have been usedclinically as hypoglycemic agents. However, all three classes ofcompound have side effects. The biguanides, for example metformin, areunspecific and in certain cases have been associated with lacticacidosis, and need to be given over a longer period of time, i.e. theyare not suitable for acute administration (C. J. Bailey et al., videsupra). The sulfonylureas, though having good hypoglycemic activity,require great care during use because they frequently cause serioushypoglycemia and are most effective over a period of circa ten years.The thiazolidinediones may cause weight gain following chronicadministration (G. L. Plosker and D. Faulds, vide supra) andtroglitazone has been associated with the occurrence of serious hepaticdysfunction.

Thus, there is a significant and rising need for antidiabetic drugs thathave novel mechanisms of action, thereby avoiding side effects producedby known therapies. The hormone somatostatin (SST) is primarily producedin the intestinal tract and in the pancreas. In addition it acts as aneurotransmitter. The hormone is involved through its receptors in theregulation of several other hormones and in immunoregulation. Inparticular, SST suppresses the secretion of insulin by pancreatic βcells and the secretion of glucagon-like peptide 1 (GLP-1) by L cells.GLP-1 in turn is one of the most potent stimulators of insulinproduction and secretion and is a trophic factor for β cells. β and Lcells express SST receptor subtype 5 (SSTR5) and agonizing this receptorsuppresses insulin and GLP-1 secretion in humans and in animal models(e.g., Y. Zambre, Z. Ling, M.-C. Chen, X. Hou, C.-W. Woon, M. Culler, J.E. Taylor, D. H. Coy, C. van Schravendijk, F. Schuit, D. G. Pipeleersand D. L. Eizirik Biochem. Pharmacol. 1999, 57, 1159-1164; S. P. Fagan,A. Azizzadeh, S. Moldovan, M. K. Ray, T. E. Adrian, X. Ding, D. H. Coyand F. C. Brunicardi Surgery 1998, 124, 254-258; M. Norman, S. Moldovan,V. Seghers, X.-P. Wang, F. J. DeMayo and F. C. Brunicardi Ann. Surg.2002, 235, 767-774; T. A. Tirone, M. A. Norman, S. Moldovan, F. J.DeMayo, X.-P. Wang and F. C. Brunicardi Pancreas 2003, 26, e67-73; M. Z.Strowski, M. Köhler, H. Y. Chen, M. E. Trumbauer, Z. Li, D. Szalkowski,S. Gopal-Truter, J. K. Fisher, J. M. Schaeffer, A. D. Blake, B. B. Zhangand H. A. Wilkinson Mol. Endocrinol. 2003, 17, 93-106).

Consequently, antagonizing the effect of SST would lead to higher plasmainsulin concentrations. In patients suffering from impaired glucosetolerance and NIDDM, a higher plasma insulin concentration wouldmoderate the dangerous hyperglycemia and accordingly reduce the risk oftissue damage. If such SSTR5 antagonists are sufficiently selective overthe other four SST receptors, little influence is expected on secretionof other hormones. Particularly, selectivity over SST receptor subtype 2avoids influences on glucagon secretion (K. Cejvan, D. H. Coy and S.Efendic Diabetes 2003, 52, 1176-1181; M. Z. Strowski, R. M. Parmar, A.D. Blake and J. M. Schaeffer Endocrinology 2000, 141, 111-117).Advantageous over established therapies is the dual mechanism of actionto increase insulin secretion: directly on pancreatic a cells andindirectly through GLP-1 release from L cells. Additionally, SSTR5knockout mice demonstrated higher insulin sensitivity than littermates(M. Z. Strowski, M. Köhler et al., vide supra). Therefore, SSTR5antagonists could have the potential to beneficially influence insulinresistance in patients with NIDDM. In summary, SSTR5 antagonists areexpected to beneficially influence NIDDM, the underlying impairedfasting glucose and impaired glucose tolerance, as well as complicationsof long-standing, insufficiently controlled diabetes mellitus.

GLP-1 is known as an endogenous regulator of gastrointestinal motilityand of food intake reducing appetite as shown in laboratory animals,healthy volunteers and patients with NIDDM (E. Näslund, B. Barkeling, N.King, M. Gutniak, J. E. Blundell, J. J. Holst, S. Rössner and P. M.Hellström Int. J. Obes. 1999, 23, 304-311; J.-P. Gutzwiller, B. Göke, J.Drewe, P. Hildebrand, S. Ketterer, D. Handschin, R. Winterhalder, D.Conen and C. Beglinger Gut 1999, 44, 81-88; J.-P. Gutzwiller, J. Drewe,B. Göke, H. Schmidt, B. Rohrer, J. Lareida and C. Beglinger Am. J.Physiol. 1999, 276, R1541-1544; M. D. Turton, D. O'Shea, I. Gunn, S. A.Beak, C. M. Edwards, K. Meeran, S. J. Choi, G. M. Taylor, M. M. Heath,P. D. Lambert, J. P. Wilding, D. M. Smith, M. A. Ghatei, J. Herbert andS. R. Bloom Nature 1996, 379, 69-72; A. Flint, A. Raben, A. Astrup andJ. J. Holst J. Clin. Invest. 1998, 101, 515-520; M. B. Toft-Nielsen, S.Madsbad and J. J. Holst Diabetes Care 1999, 22, 1137-1143; P. K.Cheikani, A. C. Haver and R. D. Reidelberger Am. J. Physiol. 2005, 288,R1695-R1706; T. Miki, K. Minami, H. Shinozaki, K. Matsumura, A. Saraya,H. Ikeda, Y. Yamada, J. J. Holst and S. Seino Diabetes 2005, 54,1056-1063); thus, elevated GLP-1 will also counteract obesity, a typicalcondition associated with and leading to NIDDM.

GLP-1 is co-secreted with GLP-2 that is, consequently, also regulated bySST through SSTR5 (L. Hansen, B. Hartmann, T. Bisgaard, H. Mineo, P. N.Jørgensen and J. J. Holst Am. J. Phys. 2000, 278, E1010-1018). GLP-2 isenterotrophic and beneficial in patients with malabsorption of certainorigins, such as short bowel syndrome (D. G. Burrin, B. Stoll and X.Guan Domest. Anim. Endocrinol. 2003, 24, 103-122; K. V. Haderslev, P. B.Jeppesen, B. Hartmann, J. Thulesen, H. A. Sorensen, J. Graff, B. S.Hansen, F. Tofteng, S. S. Poulsen, J. L. Madsen, J. J. Holst, M. Staunand P. B. Mortensen Scand. J. Gastroenterol. 2002, 37, 392-398; P. B.Jeppesen J. Nutr. 2003, 133, 3721-3724).

Moreover, there is increasing evidence for a role of SST on immune cellsand expression of SSTR5 on activated T lymphocytes (T. Talme, J.Ivanoff, M. Hägglund, R. J. J. van Neerven, A. Ivanoff and K. G.Sundqvist Clin. Exp. Immunol. 2001, 125, 71-79; D. Ferone, P. M. vanHagen, C. Semino, V. A. Dalm, A. Barreca, A. Colao, S. W. J. Lamberts,F. Minuto and L. J. Hofland Dig. Liver Dis. 2004, 36, S68-77; C. E.Ghamrawy, C. Rabourdin-Combe and S. Krantic Peptides 1999, 20, 305-311).Consequently, SSTR5 antagonists could also prove valuable in treatingdiseases characterized by a disturbed immune system, such asinflammatory bowel disease.

SUMMARY OF THE INVENTION

In an embodiment of the present invention, provided is a compound offormula (I):

wherein

-   A is —O— or —NH—;-   R¹ is selected from the group consisting of hydrogen, C₁₋₇-alkoxy    and halogen;-   R² is selected from the group consisting of C₂₋₇-alkyl,    C₂₋₇-alkenyl, halogen-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl, and    benzyl;-   R³ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,-   hydroxy, C₁₋₇-alkoxy, C₂₋₇-alkenyloxy,-   hydroxy-C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkoxy,-   —O—C₃₋₇-cycloalkyl,-   halogen, halogen-C₁₋₇-alkyl, halogen-C₁₋₇-alkoxy,-   —C(O)OR⁶, wherein R⁶ is C₁₋₇-alkyl,-   amino, pyrrolyl,-   unsubstituted phenyl or phenyl substituted by one to three groups    independently selected from C₁₋₇-alkyl, halogen and C₁₋₇-alkoxy;-   R⁴ is selected from the group consisting of hydrogen, hydroxy,    C₁₋₇-alkoxy, amino, nitro, hydroxy-C₁₋₇-alkoxy,    C₁₋₇-alkoxy-C₁₋₇-alkoxy, and —O-benzyl;-   or R³ and R⁴ are bonded to each other to form a ring together with    the carbon atoms they are attached to and R³ and R⁴ together are    —O—C(CH₃)₂—CH═CH—;-   R⁵ is selected from the group consisting of hydrogen, halogen and    C₁₋₇-alkoxy;-   G is selected from the groups

wherein

-   R⁷ and R¹¹ are hydrogen;-   R⁸ and R¹⁰ independently from each other are hydrogen or    —NH—C(O)—R²⁵, wherein R²⁵ is C₁₋₇-alkyl;-   R⁹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,-   halogen, halogen-C₁₋₇-alkyl, cyano,-   —C(O)OR²⁶, wherein R²⁶ is hydrogen or C₁₋₇-alkyl,-   —(CH₂)_(m)—S(O)₂—NH—R²⁷, wherein m is 0 or 1 and R²⁷ is selected    from C₁₋₇-alkyl, unsubstituted heteroaryl and heteroaryl substituted    by C₁₋₇-alkyl; and-   —NH—S(O)₂—R²⁸, wherein R²⁸ is C₁₋₇-alkyl; or-   or R⁸ and R⁹ are bonded to each other to form a ring together with    the carbon atoms they are attached to and R⁸ and R⁹ together are    —CH₂—S(O)₂—CH₂—;-   R¹² is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    halogen and amino;-   R¹³ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    halogen,-   halogen-C₁₋₇-alkyl, cyano, nitro, phenyl, tetrazolyl,    benzoimidazolyl,-   —COOR²⁹, wherein R²⁹ is hydrogen or C₁₋₇-alkyl,-   hydroxy-C₁₋₇-alkoxy, cyano-C₁₋₇-alkoxy,-   —CONHR³⁰, wherein R³⁰ is selected from the group consisting of    hydrogen,-   C₁₋₇-alkyl, C₃₋₇-cycloalkyl, hydroxy-C₁₋₇-alkyl,    C₁₋₇-alkoxy-C₁₋₇-alkyl,-   halogen-C₁₋₇-alkyl, carboxy-C₁₋₇-alkyl,-   —(CH₂)_(n)—NH—C(O)—R³¹, wherein n is 1 or 2 and R³¹ is C₁₋₇-alkyl,-   —S(O)₂—R³³, wherein R³³ is C₁₋₇-alkyl,-   —O—S(O)₂—R³⁴, wherein R³⁴ is C₁₋₇-alkyl, and-   —CO-heterocyclyl, wherein heterocyclyl is a ring selected from    pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, said ring    being unsubstituted or substituted by a group selected from hydroxy,    carboxy, carbamoyl and C₁₋₇-alkanoyl;-   R¹⁴ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    C₁₋₇-alkoxy,-   C₁₋₇-alkoxy-C₁₋₇-alkyl, cyano, carbamoyl,-   —COOR³⁵, wherein R³⁵ is hydrogen or C₁₋₇-alkyl,-   halogen and halogen-C₁₋₇-alkyl;-   R¹⁵ is selected from the group consisting of hydrogen, cyano,    halogen and-   halogen-C₁₋₇-alkyl;-   R¹⁶ and R¹⁸ are hydrogen;-   R¹⁷ is carbamoyl or —COOR³², wherein R³² is hydrogen or C₁₋₇-alkyl;-   R¹⁹ is hydrogen or halogen;-   R²⁰ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkyl and halogen;-   R²¹, R²² and R²³ independently from each other are hydrogen or    halogen;-   R²⁴ is hydrogen or C₁₋₇-alkyl;    and pharmaceutically acceptable salts thereof.

In another embodiment of the present invention, provided is a processfor the manufacture of compounds according to formula I, comprising thesteps of:

a) reacting a compound of the general formulaG-X  IIwherein G is as defined above and G is a leaving group,with a compound of the formula

wherein A and R¹ to R⁵ are as defined above,to obtain a compound of the formula

and, if desired, converting the compound of formula I into apharmaceutically acceptable salt;or, alternatively,b) reacting a compound of the general formula

wherein G is as defined above,with an aldehyde of the formula

wherein A and R¹ to R⁵ are as defined above,by employing a reducing agent to obtain a compound of the formula

and, if desired, converting the compound of formula I into apharmaceutically acceptable salt.

In a further embodiment of the present invention, provided is apharmaceutical composition, comprising a therapeutically effectiveamount of a compound according to formula I as well as apharmaceutically acceptable carrier and/or adjuvant.

In a yet another embodiment of the present invention, provided is amethod for the treatment of diseases which are associated with themodulation of SST receptors subtype 5, comprising the step ofadministering a therapeutically effective amount of a compound accordingto formula I to a human being or animal in need thereof.

DETAILED DESCRIPTION

Provided herein are selective, directly acting SSTR5 antagonists. Suchantagonists are useful as therapeutically active substances,particularly in the treatment and/or prevention of diseases which areassociated with the modulation of SST receptors subtype 5.

In the present description the term “alkyl”, alone or in combinationwith other groups, refers to a branched or straight-chain monovalentsaturated aliphatic hydrocarbon radical of one to twenty carbon atoms,preferably one to sixteen carbon atoms, more preferably one to tencarbon atoms.

The term “lower alkyl” or “C₁₋₇-alkyl”, alone or in combination,signifies a straight-chain or branched-chain alkyl group with 1 to 7carbon atoms, preferably a straight or branched-chain alkyl group with 1to 4 carbon atoms. Examples of straight-chain and branched C₁-C₇ alkylgroups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, the isomeric pentyls, the isomeric hexyls and the isomericheptyls, preferably methyl, ethyl and isopropyl, and most preferred thegroups specifically exemplified herein.

The term “lower alkenyl” or “C₂₋₇-alkenyl”, alone or in combination,signifies a straight-chain or branched hydrocarbon residue comprising anolefinic bond and up to 7, preferably up to 6, particularly preferred upto 4 carbon atoms. Examples of alkenyl groups are ethenyl, 1-propenyl,2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl.A preferred example is 2-propenyl (allyl).

The term “cycloalkyl” or “C₃₋₇-cycloalkyl” refers to a monovalentcarbocyclic radical of three to seven, preferably three to five carbonatoms. This term is further exemplified by radicals such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, with cyclobutylbeing especially preferred.

The term “alkoxy” refers to the group R′—O—, wherein R′ is alkyl. Theterm “lower alkoxy” or “C₁₋₇-alkoxy” refers to the group R′—O—, whereinR′ is lower alkyl and the term “lower alkyl” has the previously givensignificance. Examples of lower alkoxy groups are e.g., methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy,preferably methoxy and ethoxy and most preferred the groups specificallyexemplified herein.

The term “lower alkoxyalkyl” or “C₁₋₇-alkoxy-C₁₋₇-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by an alkoxy group as definedabove. Among the preferred lower alkoxyalkyl groups are methoxymethyl,methoxyethyl and ethoxymethyl.

The term “lower alkoxyalkoxy” or “C₁₋₇-alkoxy-C₁₋₇-alkoxy” refers tolower alkoxy groups as defined above wherein at least one of thehydrogen atoms of the lower alkoxy group is replaced by an alkoxy groupas defined above. Among the preferred lower alkoxyalkoxy groups are2-methoxy-ethoxy and 3-methoxy-propoxy.

The term “halogen” refers to fluorine, chlorine, bromine and iodine,with fluorine, chlorine and bromine being preferred.

The term “lower halogenalkyl” or “halogen-C₁₋₇-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a halogen atom, preferablyfluoro or chloro, most preferably fluoro. Among the preferredhalogenated lower alkyl groups are trifluoromethyl, difluoromethyl,difluoroethyl, fluoromethyl and chloromethyl, with trifluoromethyl anddifluoroethyl being especially preferred.

The term “lower halogenalkoxy” or “halogen-C₁₋₇-alkoxy” refers to loweralkoxy groups as defined above wherein at least one of the hydrogenatoms of the lower alkoxy group is replaced by a halogen atom,preferably fluoro or chloro, most preferably fluoro. Among the preferredhalogenated lower alkyl groups are trifluoromethoxy, difluoromethoxy,fluoromethoxy and chloromethoxy, with trifluoromethoxy being especiallypreferred.

The term “lower hydroxyalkyl” or “hydroxy-C₁₋₇-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a hydroxy group. Examples oflower hydroxyalkyl groups are hydroxymethyl or hydroxyethyl, but alsogroups having two hydroxy groups such as 1,3-dihydroxy-2-propyl.

The term “lower hydroxyalkoxy” or “hydroxy-C₁₋₇-alkoxy” refers to loweralkoxy groups as defined above wherein at least one of the hydrogenatoms of the lower alkoxy group is replaced by a hydroxy group. Examplesof lower hydroxyalkoxy groups are hydroxymethoxy or hydroxyethoxy, butalso dihydroxyalkoxy groups such as 2,3-dihydroxy-propyl-1-oxy.

The term “heteroaryl” refers to an aromatic 5- or 6-membered ring whichcan comprise one, two or three atoms selected from nitrogen, oxygenand/or sulphur. Examples of heteroaryl groups are furyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, isoxazolyl, thiazolyl,isothiazolyl, oxazolyl, imidazolyl, pyrazolyl, triazolyl, oxadiazolyl,oxatriazolyl, tetrazolyl, pentazolyl, or pyrrolyl. The heteroaryl groupcan optionally be mono- or disubstituted by lower alkyl. The term“heteroaryl” also includes bicyclic aromatic moieties having 9 to 10ring atoms with 1 to 3 heteroatoms such as benzofuranyl, benzothiazolyl,indolyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzisoxazolyl, and benzothienyl. Preferred heteroaryl groups areisoxazolyl, tetrazolyl and benzoimidazolyl which groups can optionallybe mono- or disubstituted by lower alkyl. Especially preferred isisoxazolyl which can optionally be substituted by lower alkyl.

The term “heterocyclyl” in general refers to a saturated or partlyunsaturated ring which can comprise one, two or three atoms selectedfrom nitrogen, oxygen and/or sulphur. Examples of heterocyclyl ringsinclude aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,tetrahydropyridyl, azepinyl, piperazinyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl,thiazolidinyl, isothiazolidinyl, thiadiazolylidinyl, dihydrofuryl,tetrahydrofuryl, oxiranyl, oxetanyl, dihydropyranyl, tetrahydropyranyland thiomorpholinyl. Preferred heterocyclyl groups are pyrrolidinyl,piperidinyl, piperazinyl and morpholinyl.

The term “lower alkanoyl” refers to the group —CO—R′, wherein R′ islower alkyl and the term “lower alkyl” has the previously givensignificance. Preferred is a group —CO—R′, wherein R′ is methyl, meaningan acetyl group.

The term “carbamoyl” refers to the group —CO—NH₂.

The term “carboxy” refers to the group —COOH.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, preferably hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleicacid, malonic acid, salicylic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, N-acetylcysteine and the like. In addition these saltsmay be prepared form addition of an inorganic base or an organic base tothe free acid. Salts derived from an inorganic base include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium, magnesiumsalts and the like. Salts derived from organic bases include, but arenot limited to salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymineresins and the like. The compound of formula I can also be present inthe form of zwitterions. Particularly preferred pharmaceuticallyacceptable salts of compounds of formula I are the hydrochloride salts.

The compounds of formula I can also be solvated, e.g., hydrated. Thesolvation can be effected in the course of the manufacturing process orcan take place e.g. as a consequence of hygroscopic properties of aninitially anhydrous compound of formula I (hydration). The termpharmaceutically acceptable salts also includes physiologicallyacceptable solvates.

“Isomers” are compounds that have identical molecular formulae but thatdiffer in the nature or the sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereoisomers”, and stereoisomers that are non-superimposable mirrorimages are termed “enantiomers”, or sometimes optical isomers. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”.

In detail, the present invention relates to compounds of the generalformula I

wherein

-   A is —O— or —NH—;-   R¹ is selected from the group consisting of hydrogen, C₁₋₇-alkoxy    and halogen;-   R² is selected from the group consisting of C₂₋₇-alkyl,    C₂₋₇-alkenyl, halogen-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl, and    benzyl;-   R³ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    -   hydroxy, C₁₋₇-alkoxy, C₂₋₇-alkenyloxy,    -   hydroxy-C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkoxy,    -   —O—C₃₋₇-cycloalkyl,    -   halogen, halogen-C₁₋₇-alkyl, halogen-C₁₋₇-alkoxy,    -   —C(O)OR⁶, wherein R⁶ is C₁₋₇-alkyl,    -   amino, pyrrolyl,    -   unsubstituted phenyl or phenyl substituted by one to three        groups independently selected from C₁₋₇-alkyl, halogen and        C₁₋₇-alkoxy;-   R⁴ is selected from the group consisting of hydrogen, hydroxy,    C₁₋₇-alkoxy, amino, nitro, hydroxy-C₁₋₇-alkoxy,    C₁₋₇-alkoxy-C₁₋₇-alkoxy, and —O-benzyl;-   or R³ and R⁴ are bonded to each other to form a ring together with    the carbon atoms they are attached to and R³ and R⁴ together are    —O—C(CH₃)₂—CH═CH—;-   R⁵ is selected from the group consisting of hydrogen, halogen and    C₁₋₇-alkoxy;-   G is selected from the groups

wherein

-   R⁷ and R¹¹ are hydrogen;-   R⁸ and R¹⁰ independently from each other are hydrogen or    —NH—C(O)—R²⁵, wherein R²⁵ is C₁₋₇-alkyl;-   R⁹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    -   halogen, halogen-C₁₋₇-alkyl, cyano,    -   —C(O)OR²⁶, wherein R²⁶ is hydrogen or C₁₋₇-alkyl,    -   —(CH₂)_(m)—S(O)₂—NH—R²⁷, wherein m is 0 or 1 and R²⁷ is selected        from C₁₋₇-alkyl, unsubstituted heteroaryl and heteroaryl        substituted by C₁₋₇-alkyl; and    -   —NH—S(O)₂—R²⁸, wherein R²⁸ is C₁₋₇-alkyl; or-   or R⁸ and R⁹ are bonded to each other to form a ring together with    the carbon atoms they are attached to and R⁸ and R⁹ together are    —CH₂—S(O)₂—CH₂—;-   R¹² is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    halogen and amino;-   R¹³ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    halogen,    -   halogen-C₁₋₇-alkyl, cyano, nitro, phenyl, tetrazolyl,        benzoimidazolyl,    -   —COOR²⁹, wherein R²⁹ is hydrogen or C₁₋₇-alkyl,    -   hydroxy-C₁₋₇-alkoxy, cyano-C₁₋₇-alkoxy,    -   —CONHR³⁰, wherein R³⁰ is selected from the group consisting of        hydrogen,    -   C₁₋₇-alkyl, C₃₋₇-cycloalkyl, hydroxy-C₁₋₇-alkyl,        C₁₋₇-alkoxy-C₁₋₇-alkyl, halogen-C₁₋₇-alkyl, carboxy-C₁₋₇-alkyl,    -   —(CH₂)_(n)—NH—C(O)—R³¹, wherein n is 1 or 2 and R³¹ is        C₁₋₇-alkyl,    -   —S(O)₂—R³³, wherein R³³ is C₁₋₇-alkyl,    -   —O—S(O)₂—R³⁴, wherein R³⁴ is C₁₋₇-alkyl, and    -   —CO-heterocyclyl, wherein heterocyclyl is a ring selected from        pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, said        ring being unsubstituted or substituted by a group selected from        hydroxy, carboxy, carbamoyl and C₁₋₇-alkanoyl;-   R¹⁴ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkyl, cyano, carbamoyl,    -   —COOR³⁵, wherein R³⁵ is hydrogen or C₁₋₇-alkyl,    -   halogen and halogen-C₁₋₇-alkyl;-   R¹⁵ is selected from the group consisting of hydrogen, cyano,    halogen and halogen-C₁₋₇-alkyl;-   R¹⁶ and R^(1g) are hydrogen;-   R¹⁷ is carbamoyl or —COOR³², wherein R³² is hydrogen or C₁₋₇-alkyl;-   R¹⁹ is hydrogen or halogen;-   R²⁰ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkyl and halogen;-   R²¹, R²² and R²³ independently from each other are hydrogen or    halogen;-   R²⁴ is hydrogen or C₁₋₇-alkyl;    and pharmaceutically acceptable salts thereof.

Preferred compounds of formula I of the present invention are alsothose, wherein A is O.

Also preferred are compounds of formula I, wherein A is NH.

Furthermore, compounds of formula I according to the present inventionare preferred, wherein R¹ is hydrogen.

Also preferred are compounds of formula I according to the invention,wherein R² is selected from the group consisting of C₂₋₇-alkyl,C₂₋₇-alkenyl and halogen-C₁₋₇-alkyl. Especially preferred are thosecompounds of formula I, wherein R² is selected from the group consistingof ethyl, propyl, isopropyl, allyl, 2-fluoroethyl, butyl and isobutyl,with those compounds, wherein R² is ethyl or isopropyl, being mostpreferred.

Further preferred compounds of formula I according to the presentinvention are those, wherein R³ is selected from the group consisting ofhydrogen, C₁₋₇-alkyl, hydroxy, C₁₋₇-alkoxy, halogen,halogen-C₁₋₇-alkoxy, —C(O)OR⁶, wherein R⁶ is C₁₋₇-alkyl, amino andpyrrolyl. More preferred are those compounds of formula I, wherein R³ isselected from the group consisting of hydrogen, C₁₋₇-alkoxy and halogen,with those compounds, wherein R³ is halogen, being especially preferred.Most preferably, R³ is chloro.

Also preferred are compounds of formula I, wherein R³ is unsubstitutedphenyl or phenyl substituted by one to three groups independentlyselected from C₁₋₇-alkyl, halogen and C₁₋₇-alkoxy, with those compoundsof formula I, wherein R³ is phenyl substituted by halogen being morepreferred, and with compounds of formula I, wherein R³ is 4-fluorophenylor 4-chlorophenyl being most preferred.

Furthermore, compounds of formula I of the present invention arepreferred, wherein R⁴ is selected from the group consisting of hydrogen,hydroxy, C₁₋₇-alkoxy and C₁₋₇-alkoxy-C₁₋₇-alkoxy.

Another group of preferred compounds of formula I according to thepresent invention are those, wherein R³ and R⁴ are bonded to each otherto form a ring together with the carbon atoms they are attached to andR³ and R⁴ together are

—O—C(CH₃)₂—CH═CH—. These are compounds of the formula Ix:

Furthermore, compounds of formula I according to the invention arepreferred, wherein R⁵ is hydrogen.

Especially preferred are compounds of formula I according to the presentinvention, wherein G is

and wherein

-   R⁷ and R¹¹ are hydrogen;-   R⁸ and R¹⁰ independently from each other are hydrogen or    —NH—C(O)—R²⁵, wherein R²⁵ is C₁₋₇-alkyl; and-   R⁹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    halogen, halogen-C₁₋₇-alkyl, cyano,-   —C(O)OR²⁶, wherein R²⁶ is hydrogen or C₁₋₇-alkyl,-   —(CH₂)_(m)—S(O)₂—NH—R²⁷, wherein m is 0 or 1 and R²⁷ is selected    from C₁₋₇-alkyl, unsubstituted heteroaryl and heteroaryl substituted    by C₁₋₇-alkyl; and-   —NH—S(O)₂—R²⁸, wherein R²⁸ is C₁₋₇-alkyl; or-   R⁸ and R⁹ are bonded to each other to form a ring together with the    carbon atoms they are attached to and R⁸ and R⁹ together are    —CH₂—S(O)₂—CH₂—.    Within this group, those compounds of formula I are preferred,    wherein-   R⁷, R⁸, R¹⁰ and R¹¹ are hydrogen; and-   R⁹ is selected from the group consisting of C₁₋₇-alkyl,-   halogen, halogen-C₁₋₇-alkyl, cyano,-   —C(O)OR²⁶, wherein R²⁶ is hydrogen or C₁₋₇-alkyl,-   —(CH₂)_(m)—S(O)₂—NH—R²⁷, wherein m is 0 or 1 and R²⁷ is selected    from C₁₋₇-alkyl, unsubstituted heteroaryl and heteroaryl substituted    by C₁₋₇-alkyl; and-   —NH—S(O)₂—R²⁸, wherein R²⁸ is C₁₋₇-alkyl.

Another group of preferred compounds of formula I according to theinvention are those, wherein G is

and wherein

-   R¹² is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    halogen and amino;-   R¹³ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    halogen, halogen-C₁₋₇-alkyl, cyano, nitro, phenyl, tetrazolyl,    benzoimidazolyl,-   —COOR²⁹, wherein R²⁹ is hydrogen or C₁₋₇-alkyl,-   hydroxy-C₁₋₇-alkoxy, cyano-C₁₋₇-alkoxy,-   —CONHR³⁰, wherein R³⁰ is selected from the group consisting of    hydrogen,-   C₁₋₇-alkyl, C₃₋₇-cycloalkyl, hydroxy-C₁₋₇-alkyl,    C₁₋₇-alkoxy-C₁₋₇-alkyl,-   halogen-C₁₋₇-alkyl, carboxy-C₁₋₇-alkyl,-   —(CH₂)_(n)—NH—C(O)—R³¹, wherein n is 1 or 2 and R³¹ is C₁₋₇-alkyl,-   —S(O)₂—R³³, wherein R³³ is C₁₋₇-alkyl,-   —O—S(O)₂—R³⁴, wherein R³⁴ is C₁₋₇-alkyl, and-   —CO-heterocyclyl, wherein heterocyclyl is a ring selected from    pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, said ring    being unsubstituted or substituted by a group selected from hydroxy,    carboxy, carbamoyl and C₁₋₇-alkanoyl;-   R¹⁴ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkyl, cyano, carbamoyl,-   —COOR³⁵, wherein R³⁵ is hydrogen or C₁₋₇-alkyl,-   halogen and halogen-C₁₋₇-alkyl; and-   R¹⁵ is selected from the group consisting of hydrogen, cyano,    halogen and halogen-C₁₋₇-alkyl.    Within this group, those compounds are preferred, wherein R¹², R¹⁴    and R¹⁵ are hydrogen; and-   R¹³ is selected from the group consisting of C₁₋₇-alkyl, halogen,-   halogen-C₁₋₇-alkyl, cyano, nitro, phenyl, tetrazolyl,    benzoimidazolyl,-   —COOR²⁹, wherein R²⁹ is hydrogen or C₁₋₇-alkyl,-   —CONHR³⁰, wherein R³⁰ is selected from the group consisting of    hydrogen,-   C₁₋₇-alkyl, C₃₋₇-cycloalkyl, hydroxy-C₁₋₇-alkyl,    C₁₋₇-alkoxy-C₁₋₇-alkyl,-   halogen-C₁₋₇-alkyl, carboxy-C₁₋₇-alkyl,-   —(CH₂)_(n)—NH—C(O)—R³¹, wherein n is 1 or 2 and R³¹ is C₁₋₇-alkyl,    and-   —CO-heterocyclyl, wherein heterocyclyl is a ring selected from    pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, said ring    being unsubstituted or substituted by a group selected from hydroxy,    carboxy, carbamoyl and C₁₋₇-alkanoyl.

A further group of preferred compounds of formula I according to theinvention are those, wherein G is

and wherein

-   R¹⁶ and R¹⁸ are hydrogen; and-   R¹⁷ is carbamoyl or —COOR³², wherein R³² is hydrogen or C₁₋₇-alkyl.

Also preferred are compounds of formula I according to the invention,wherein G is a group selected from

and wherein

-   R¹⁹ is hydrogen or halogen;-   R²⁰ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkyl and halogen; and-   R²¹, R²² and R²³ independently from each other are hydrogen or    halogen.

Another group of preferred compounds are those, wherein G is

and wherein R²⁴ is hydrogen or C₁₋₇-alkyl.

In one aspect, the invention relates to compounds of formula I havingthe formula

wherein

-   A is —O— or —NH—;-   R¹ is selected from the group consisting of hydrogen, C₁₋₇-alkoxy    and halogen;-   R² is selected from the group consisting of C₂₋₇-alkyl,    C₂₋₇-alkenyl, halogen-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl, and    benzyl;-   R³ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,-   hydroxy, C₁₋₇-alkoxy, C₂₋₇-alkenyloxy,-   hydroxy-C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkoxy,-   —O—C₃₋₇-cycloalkyl,-   halogen, halogen-C₁₋₇-alkyl, halogen-C₁₋₇-alkoxy,-   —C(O)OR⁶, wherein R⁶ is C₁₋₇-alkyl,-   amino and pyrrolyl;-   R⁴ is selected from the group consisting of hydrogen, hydroxy,    C₁₋₇-alkoxy, amino, nitro, hydroxy-C₁₋₇-alkoxy,    C₁₋₇-alkoxy-C₁₋₇-alkoxy, and —O-benzyl;-   or R³ and R⁴ are bonded to each other to form a ring together with    the carbon atoms they are attached to and R³ and R⁴ together are    —O—C(CH₃)₂—CH═CH—;-   R⁵ is selected from the group consisting of hydrogen, halogen and    C₁₋₇-alkoxy;-   G is selected from the groups

wherein

-   R⁷ and R¹¹ are hydrogen;-   R⁸ and R¹⁰ independently from each other are hydrogen or    —NH—C(O)—R²⁵, wherein R²⁵ is C₁₋₇-alkyl;-   R⁹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    halogen, halogen-C₁₋₇-alkyl, cyano,-   —C(O)OR²⁶, wherein R²⁶ is hydrogen or C₁₋₇-alkyl,-   —(CH₂)_(m)—S(O)₂—NH—R²⁷, wherein m is 0 or 1 and R²⁷ is selected    from C₁₋₇-alkyl, unsubstituted heteroaryl and heteroaryl substituted    by C₁₋₇-alkyl; and-   —NH—S(O)₂—R²⁸, wherein R²⁸ is C₁₋₇-alkyl; or-   or R⁸ and R⁹ are bonded to each other to form a ring together with    the carbon atoms they are attached to and R¹ and R⁹ together are    —CH₂—S(O)₂—CH₂—;-   R¹² is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    halogen and amino;-   R¹³ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    halogen, halogen-C₁₋₇-alkyl, cyano, nitro, phenyl, tetrazolyl,    benzoimidazolyl,-   —COOR²⁹, wherein R²⁹ is hydrogen or C₁₋₇-alkyl,-   —CONHR³⁰, wherein R³⁰ is selected from the group consisting of    hydrogen,-   C₁₋₇-alkyl, C₃₋₇-cycloalkyl, hydroxy-C₁₋₇-alkyl,    C₁₋₇-alkoxy-C₁₋₇-alkyl,-   halogen-C₁₋₇-alkyl, carboxy-C₁₋₇-alkyl,-   —(CH₂)_(n)—NH—C(O)—R³, wherein n is 1 or 2 and R³¹ is C₁₋₇-alkyl,    and-   —CO-heterocyclyl, wherein heterocyclyl is a ring selected from    pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, said ring    being unsubstituted or substituted by a group selected from hydroxy,    carboxy, carbamoyl and C₁₋₇-alkanoyl;-   R¹⁴ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkyl, cyano, carbamoyl, halogen and    halogen-C₁₋₇-alkyl;-   R¹⁵ is selected from the group consisting of hydrogen, cyano,    halogen and halogen-C₁₋₇-alkyl;-   R¹⁶ and R¹⁸ are hydrogen;-   R¹⁷ is carbamoyl or —COOR³², wherein R³² is hydrogen or C₁₋₇-alkoxy;-   R¹⁹ is hydrogen or halogen;-   R²⁰ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,    C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkyl and halogen;-   R²¹, R²² and R²³ independently from each other are hydrogen or    halogen;-   R²⁴ is hydrogen or C₁₋₇-alkyl;    and pharmaceutically acceptable salts thereof.

Examples of preferred compounds of formula I are the following:

-   4-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-benzonitrile,-   4-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-benzonitrile,-   N-{3-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-phenyl}-acetamide,-   N-{3-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-phenyl}-acetamide,-   [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(4-ethyl-phenyl)-amine,-   C-{4-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-phenyl}-N-methyl-methanesulfonamide,-   (2,2-dioxo-2,3-dihydro-1H-2λ6-benzo[c]thiophen-5-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine,-   4-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-benzoic acid,-   4-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-N-(5-methyl-isoxazol-3-yl)-benzenesulfonamide,-   N-{4-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-phenyl}-methanesulfonamide,-   [5-(1H-benzoimidazol-2-yl)-pyridin-2-yl]-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine,-   (7-chloro-4-methoxymethyl-quinolin-2-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine,-   [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(6-fluoro-quinolin-2-yl)-amine,-   6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-nicotinonitrile,-   [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,-   (6-chloro-pyridin-2-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine,-   6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid    ethyl ester,-   6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid    methyl ester,-   [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(5-nitro-pyridin-2-yl)-amine,-   (5-bromo-pyridin-2-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine,-   [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(6-methyl-5-nitro-pyridin-2-yl)-amine,-   N⁶-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-3-nitro-pyridine-2,6-diamine,-   2-chloro-6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-isonicotinic    acid methyl ester,-   2-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-6-methyl-5-phenyl-nicotinonitrile,-   2-chloro-6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-5-fluoro-nicotinonitrile,-   [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(5-methyl-[1,6]naphthyridin-2-yl)-amine,-   {2-chloro-6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-pyridin-4-yl}-methanol,-   6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid    methyl ester,-   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,-   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(3-trifluoromethyl-pyridin-2-yl)-amine,-   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(6-methyl-5-nitro-pyridin-2-yl)-amine,-   N⁶-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-3-nitro-pyridine-2,6-diamine,-   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(6-chloro-4-methoxymethyl-pyridin-2-yl)-amine,-   2-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-6-methyl-nicotinonitrile,-   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(6-fluoro-quinolin-2-yl)-amine,-   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(5-methyl-[1,6]naphthyridin-2-yl)-amine,-   6-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-nicotinonitrile,-   6-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-nicotinonitrile,-   6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-nicotinonitrile,-   6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-nicotinonitrile,-   6-[1-(3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinonitrile,-   6-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamino]-nicotinonitrile,-   6-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-nicotinonitrile,-   6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinonitrile,-   6-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinonitrile,-   6-[1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinonitrile,-   6-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-ylamino]-nicotinonitrile,-   6-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-nicotinamide,-   6-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-nicotinamide,-   6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,-   6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-nicotinamide,-   6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,-   6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,-   6-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,-   6-[1-(3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,-   6-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,-   6-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-nicotinamide,-   6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,-   6-[1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,-   6-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-ylamino]-nicotinamide,-   6-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-nicotinic acid,-   6-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-nicotinic acid,-   6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid,-   6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-nicotinic    acid,-   6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-nicotinic    acid,-   6-[1-(3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid,-   6-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid,-   6-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-nicotinic    acid,-   6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinic    acid,-   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-[5-(1H-tetrazol-5-yl)-pyridin-2-yl]-amine,-   [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-[5-(1H-tetrazol-5-yl)-pyridin-2-yl]-amine,-   [1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-[5-(1H-tetrazol-5-yl)-pyridin-2-yl]-amine,-   [1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-[5-(1H-tetrazol-5-yl)-pyridin-2-yl]-amine,-   [1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-[5-(1H-tetrazol-5-yl)-pyridin-2-yl]-amine,-   [1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,-   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,-   [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,-   [1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,-   [1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,-   [1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,-   [1-(3,5-diethoxy-4-iodo-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,-   [1-(3-ethoxy-4-iodo-5-methoxymethoxy-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,-   [1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,-   6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinic    acid methyl ester,-   6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinic    acid methyl ester,-   6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinic    acid methyl ester,-   6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinic    acid methyl ester,-   6-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinic    acid methyl ester,-   [1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   [1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   {1-[3-ethoxy-4-(1-ethyl-propoxy)-benzyl]-piperidin-4-yl}-quinolin-2-yl-amine,-   [1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   [1-(3-allyloxy-4-methoxy-benzyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   [1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   [1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   [1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   [1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   3-isopropoxy-5-[4-(quinolin-2-ylamino)-piperidin-1-ylmethyl]-phenol,-   [1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   [1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   [1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   [1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   [1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   [1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-(4-methyl-quinolin-2-yl)-amine,-   [1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-(4-methyl-quinolin-2-yl)-amine,-   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(4-methyl-quinolin-2-yl)-amine,-   [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(4-methyl-quinolin-2-yl)-amine,-   3-isopropoxy-5-[4-(4-methyl-quinolin-2-ylamino)-piperidin-1-ylmethyl]-phenol,-   [1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-(4-methyl-quinolin-2-yl)-amine,-   [1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-(4-methyl-quinolin-2-yl)-amine,-   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(4-methyl-quinolin-2-yl)-amine,-   [1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-(4-methyl-quinolin-2-yl)-amine,-   [1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-yl]-(4-methyl-quinolin-2-yl)-amine,-   [1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-(4-methyl-quinolin-2-yl)-amine,-   (4-chloro-quinolin-2-yl)-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-amine,-   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(4-chloro-quinolin-2-yl)-amine,-   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(4-chloro-quinolin-2-yl)-amine,-   [1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-yl]-(4-chloro-quinolin-2-yl)-amine,-   (8-chloro-quinolin-2-yl)-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-amine,-   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(8-chloro-quinolin-2-yl)-amine,-   4-[4-(8-chloro-quinolin-2-ylamino)-piperidin-1-ylmethyl]-2-ethoxy-phenol,-   (8-chloro-quinolin-2-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine,-   (8-chloro-quinolin-2-yl)-{1-[3-ethoxy-4-(1-ethyl-propoxy)-benzyl]-piperidin-4-yl}-amine,-   (8-chloro-quinolin-2-yl)-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-yl]-amine,-   [1-(3-allyloxy-4-methoxy-benzyl)-piperidin-4-yl]-(8-chloro-quinolin-2-yl)-amine,-   [1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-yl]-(8-chloro-quinolin-2-yl)-amine,-   (8-chloro-quinolin-2-yl)-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine,-   (8-chloro-quinolin-2-yl)-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-amine,-   (8-chloro-quinolin-2-yl)-[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-amine,-   4-[4-(8-chloro-quinolin-2-ylamino)-piperidin-1-ylmethyl]-2,6-diethoxy-benzoic    acid ethyl ester,-   (8-chloro-quinolin-2-yl)-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine,-   [1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-(8-chloro-quinolin-2-yl)-amine,-   (8-chloro-quinolin-2-yl)-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-amine,-   [1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-isoquinolin-1-yl-amine,-   [1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-isoquinolin-1-yl-amine,-   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-isoquinolin-1-yl-amine,-   [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-isoquinolin-1-yl-amine,    isoquinolin-1-yl-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-yl]-amine,-   [1-(3-allyloxy-4-methoxy-benzyl)-piperidin-4-yl]-isoquinolin-1-yl-amine,-   [1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-yl]-isoquinolin-1-yl-amine,-   [1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-isoquinolin-1-yl-amine,-   [1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-isoquinolin-1-yl-amine,-   [1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-isoquinolin-1-yl-amine,-   3-isopropoxy-5-[4-(isoquinolin-1-ylamino)-piperidin-1-ylmethyl]-phenol,-   [1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-isoquinolin-1-yl-amine,-   [1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-isoquinolin-1-yl-amine,-   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-isoquinolin-1-yl-amine,-   [1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-isoquinolin-1-yl-amine,-   [1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-isoquinolin-1-yl-amine,-   (3-chloro-isoquinolin-1-yl)-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-amine,-   (3-chloro-isoquinolin-1-yl)-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine,-   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(3-chloro-isoquinolin-1-yl)-amine,-   4-[4-(3-chloro-isoquinolin-1-ylamino)-piperidin-1-ylmethyl]-2-ethoxy-phenol,-   (3-chloro-isoquinolin-1-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine,-   (3-chloro-isoquinolin-1-yl)-[1-(4-difluoromethoxy-3-ethoxy-benzyl)-piperidin-4-yl]-amine,-   (3-chloro-isoquinolin-1-yl)-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-yl]-amine,-   (3-chloro-isoquinolin-1-yl)-[1-(3-ethoxy-4-isobutoxy-benzyl)-piperidin-4-yl]-amine,-   (3-chloro-isoquinolin-1-yl)-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-yl]-amine,-   [1-(3-allyloxy-4-methoxy-benzyl)-piperidin-4-yl]-(3-chloro-isoquinolin-1-yl)-amine,-   [1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-yl]-(3-chloro-isoquinolin-1-yl)-amine,-   (3-chloro-isoquinolin-1-yl)-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine,-   (3-chloro-isoquinolin-1-yl)-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-amine,-   (3-chloro-isoquinolin-1-yl)-[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-amine,-   (3-chloro-isoquinolin-1-yl)-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine,-   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(3-chloro-isoquinolin-1-yl)-amine,-   [1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-(3-chloro-isoquinolin-1-yl)-amine,-   [1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-yl]-(3-chloro-isoquinolin-1-yl)-amine,-   5-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid methyl ester,-   5-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid methyl ester,-   5-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid methyl ester,-   5-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid methyl ester,-   5-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid methyl ester,-   5-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid methyl ester,-   5-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid methyl ester,-   5-{1-[3-(2-fluoro-ethoxy)-4-methoxy-benzyl]-piperidin-4-ylamino}-pyrazine-2-carboxylic    acid methyl ester,-   5-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid methyl ester,-   5-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid methyl ester,-   5-[1-(3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid methyl ester,-   5-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid methyl ester,-   5-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid methyl ester,-   5-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid methyl ester,-   5-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid methyl ester,-   5-[1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid methyl ester,-   5-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid methyl ester,-   2-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-isonicotinonitrile,-   2-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-isonicotinamide,-   2-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-isonicotinonitrile,-   2-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-isonicotinamide,-   2-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamino]-isonicotinonitrile,-   2-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamino]-isonicotinamide,-   2-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-isonicotinonitrile,-   2-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-isonicotinamide,-   6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide,-   6-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide,-   6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide,-   6-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide,-   6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinic    acid,-   6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinic    acid,-   6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinic    acid,-   6-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinic    acid,-   5-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid amide,-   6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-N-(2-hydroxy-ethyl)-nicotinamide,-   6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-N-cyclobutyl-nicotinamide,-   ({6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridine-3-carbonyl}-amino)-acetic    acid,-   6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-N-(2-methoxy-ethyl)-nicotinamide,-   {6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridin-3-yl}-morpholin-4-yl-methanone,-   {6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridin-3-yl}-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone,-   6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-N-(2-hydroxy-1-hydroxymethyl-ethyl)-nicotinamide,-   6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-N-(2,2,2-trifluoro-ethyl)-nicotinamide,-   N-(2-acetylamino-ethyl)-6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,-   1-{6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridine-3-carbonyl}-piperidine-4-carboxylic    acid amide,-   1-(4-{6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridine-3-carbonyl}-piperazin-1-yl)-ethanone,-   1-{6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridine-3-carbonyl}-piperidine-4-carboxylic    acid,-   (3-chloro-isoquinolin-1-yl)-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-amine,-   5-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-ylamino]-pyrazine-2-carboxylic    acid methyl ester,-   [1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-(5-methanesulfonyl-pyridin-2-yl)-amine,-   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(5-methanesulfonyl-pyridin-2-yl)-amine,-   [1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-(5-methanesulfonyl-pyridin-2-yl)-amine,-   2-chloro-6-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-isonicotinic    acid methyl ester,-   2-chloro-6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-isonicotinic    acid methyl ester,-   2-chloro-6-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-ylamino]-isonicotinic    acid methyl ester,-   {6-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-ylamino]-pyridin-3-yloxy}-acetonitrile,-   3-{6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridin-3-yloxy}-propane-1,2-diol,-   3-{6-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-ylamino]-pyridin-3-yloxy}-propane-1,2-diol,-   3-{6-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-ylamino]-pyridin-3-yloxy}-propan-1-ol,-   3-{6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridin-3-yloxy}-propan-1-ol,-   methanesulfonic acid    6-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-ylamino]-pyridin-3-yl    ester,-   2-chloro-6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-isonicotinic    acid,-   2-chloro-6-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-ylamino]-isonicotinic    acid,    and pharmaceutically acceptable salts thereof.

Especially preferred are the following compounds of formula I of thepresent invention:

-   4-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-benzonitrile,-   6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,-   6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,-   6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid,-   6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinic    acid,-   [1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-[5-(1H-tetrazol-5-yl)-pyridin-2-yl]-amine,-   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-quinolin-2-yl-amine,-   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(4-methyl-quinolin-2-yl)-amine,-   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-isoquinolin-1-yl-amine,-   ({6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridine-3-carbonyl}-amino)-acetic    acid,-   {6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridin-3-yl}-morpholin-4-yl-methanone,-   1-{6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridine-3-carbonyl}-piperidine-4-carboxylic    acid,    and pharmaceutically acceptable salts thereof.

Furthermore, the pharmaceutically acceptable salts of the compounds offormula I individually constitute preferred embodiments of the presentinvention.

Compounds of formula I can have one or more asymmetric carbon atoms andcan exist in the form of optically pure enantiomers, mixtures ofenantiomers such as, for example, racemates, optically purediastereoisomers, mixtures of diastereoisomers, diastereoisomericracemates or mixtures of diastereoisomeric racemates. The opticallyactive forms can be obtained for example by resolution of the racemates,by asymmetric synthesis or asymmetric chromatography (chromatographywith a chiral adsorbents or eluant). The invention embraces all of theseforms.

It will be appreciated, that the compounds of general formula I in thisinvention may be derivatised at functional groups to provide derivativeswhich are capable of conversion back to the parent compound in vivo.Physiologically acceptable and metabolically labile derivatives, whichare capable of producing the parent compounds of general formula I invivo are also within the scope of this invention.

A further aspect of the present invention is the process for themanufacture of compounds of formula I as defined above, which processcomprises

a) reacting a compound of the general formulaG-X  IIwherein G is as defined herein before and G is a leaving group,with a compound of the formula

wherein A and R¹ to R⁵ are as defined herein before,to obtain a compound of the formula

and, if desired, converting the compound of formula I into apharmaceutically acceptable salt;or, alternatively,b) reacting a compound of the general formula

wherein G is as defined herein before,with an aldehyde of the formula

wherein A and R¹ to R⁵ are as defined herein before,by employing a reducing agent to obtain a compound of the formula

and, if desired, converting the compound of formula I into apharmaceutically acceptable salt.

The invention further relates to compounds of formula I as definedabove, when manufactured according to a process as defined above.

Suitable reducing agents are preferably selected from the groupconsisting of pyridine-BH₃ complex, NaBH(OAc)₃ and NaCNBH₃. The reactioncan be carried out under acidic conditions by using an acid such asacetic acid or formic acid or an Lewis acid (e.g., Ti(iPrO)₄, ZnCl₂) orunder basic conditions (no additive) in a suitable solvent such asdichloromethane, dichloroethane or ethanol (or mixtures thereof) atambient or elevated temperatures using conventional heating or heatingby microwave irradiation.

As described above, the compounds of formula I of the present inventioncan be used as medicaments for the treatment and/or prevention ofdiseases which are associated with the modulation of SST receptorssubtype 5.

“Diseases which are associated with the modulation of SST receptorssubtype 5” are such diseases as diabetes mellitus, particularly type IIdiabetes mellitus, impaired fasting glucose, impaired glucose tolerance,micro- and macrovascular diabetic complications, posttransplantationdiabetes mellitus in patients having type I diabetes mellitus,gestational diabetes, obesity, inflammatory bowel diseases such asCrohn's disease or ulcerative colitis, malabsorption, autoimmunediseases such as rheumatoid arthritis, osteoarthritis, psoriasis andother skin disorder, and immunodeficiencies. Microvascular diabeticcomplications include diabetic nephropathy and diabetic retinopathy,whereas macrovascular diabetes-associated complications lead to anincreased risk for myocardial infarction, stroke and limb amputations.

The use as medicament for the treatment and/or prevention of diabetesmellitus, particularly type II diabetes mellitus, impaired fastingglucose or impaired glucose tolerance is preferred.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptablecarrier and/or adjuvant.

Further, the invention relates to compounds as defined above for use astherapeutically active substances, particularly as therapeutic activesubstances for the treatment and/or prevention of diseases which areassociated with the modulation of SST receptors subtype 5.

In another embodiment, the invention relates to a method for thetreatment and/or prevention of diseases which are which are associatedwith the modulation of SST receptors subtype 5, which method comprisesadministering a compound of formula I to a human or animal. The methodfor the treatment and/or prevention of diabetes mellitus, particularlytype II diabetes mellitus, impaired fasting glucose or impaired glucosetolerance, is most preferred.

The invention further relates to the use of compounds as defined abovefor the treatment and/or prevention of diseases which are associatedwith the modulation of SST receptors subtype 5.

In addition, the invention relates to the use of compounds as definedabove for the preparation of medicaments for the treatment and/orprevention of diseases which are associated with the modulation of SSTreceptors subtype 5. Preferred examples of such diseases are diabetesmellitus, particularly type II diabetes mellitus, impaired fastingglucose or impaired glucose tolerance.

The compounds of formula I can be manufactured by the methods givenbelow, by the methods given in the examples or by analogous methods.Appropriate reaction conditions for the individual reaction steps arestandard reactions and are known to a person skilled in the art.Starting materials are either commercially available or can be preparedby methods analogous to the methods given below, by methods described inreferences cited in the text or in the examples, or by methods known inthe art.

The synthesis of compounds with the general structure I, particularlycompounds according to formula Ia and Ib, are described in Schemes 1 to6.

The synthesis of compounds of the general formula I, particularlycompounds according to formula Ia can be accomplished according toScheme 1.

Reductive N-alkylation of suitably protected piperidines (for protectinggroups see Protective Groups in Organic Synthesis, T. W. Greene and P.G. M. Wuts, 3^(rd) Edition, 1999, Wiley-Interscience) of formula I withaldehydes 2 in the presence of a reducing agent such as pyridine-BH₃complex, NaBH(OAc)₃ or NaCNBH₃ under acidic conditions (e.g., aceticacid, formic acid), by using a Lewis acid (e.g., Ti(iPrO)₄, ZnCl₂) orunder buffered conditions, e.g., in the presence of acetic acid and atertiary amine like N-ethyl-diisopropylamine or triethylamine, in asuitable solvent such as dichloromethane (DCM), dichloroethane, ethanolor isopropanol (or mixtures thereof) at ambient or elevated temperaturesusing conventional heating or heating by microwave irradiation providepiperidines of general formula 3 (Scheme 1, step a). The piperidines offormula I may thereby used either as a salt, e.g., hydrochloride orhydrobromide salt, or as the corresponding free amine. Thealkyloxycarbonyl protecting group present in compounds 3 can be removed,using e.g., 48% aqueous hydrogen bromide or 37% aqueous hydrochloricacid as reagent preferably at elevated temperatures to remove an ethylcarbamate or using trifluoroacetic acid or hydrochloric acid in asolvent like dichloromethane, dioxane or THF preferable at roomtemperature to remove a tert-butyloxycarbonyl (BOC)-protective group(see Protective Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) Edition, 1999, Wiley-Interscience), yielding 4-aminopiperidines of formula 4 (Scheme 1, step b).

Target compounds of formula Ia can be synthesized by nucleophilicreplacement reaction of 4-amino piperidines of formula 4 andfluorobenzenes of general structure 5 at elevated temperatures (Scheme1, step c), whereby R¹, R³ and/or R⁵ is an electron withdrawing groupsuch as nitrile. Thereby heating can be achieved conventionally or bymicrowave irradiation using a suitable microwave irradiation apparatus.Furthermore the reaction can be conducted in the presence of or withoutsolvent (typically an aprotic polar solvent such as DMF(N,N-dimethylformamide), DMAc (dimethylacetamide), NMP(N-methylpyrrolidon), ethylene glycol, acetonitrile or THF(tetrahydrofurane)) and in the presence of or without a tertiary aminebase such as N-ethyl diisopropylamine, triethylamine or pyridine. Thetime for the reaction may vary widely, depending on the many factors,notably the reaction temperature and the nature of the reagents.However, a period of 0.5 h to several days will usually suffice to yieldthe piperidine derivatives of formula Ia. The starting materials andsome of the intermediates of general structure 5 (e.g.,4-fluoro-benzonitrile) are known compounds and are commerciallyavailable or can be prepared by numerous methods using conventionalreaction procedures generally known in the art. The 4-amino piperidinesof formula 4 may thereby used either as a salt, e.g., hydrochloride orhydrobromide salt, or as the corresponding free amine.

Target structures of general formula Ia can also be synthesized byreductive N-alkylation of anilines 6 with suitably protected piperidinesof formula 7 (for protecting groups see Protective Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) Edition, 1999,Wiley-Interscience) in the presence of a reducing agent such aspyridine-BH₃ complex, NaBH(OAc)₃ or NaCNBH₃ under acidic conditions(e.g., acetic acid, formic acid), by using a Lewis acid (e.g.,Ti(iPrO)₄, ZnCl₂) or under buffered conditions, e.g., in the presence ofacetic acid and a tertiary amine like N-ethyl diisopropylamine ortriethylamine in a suitable solvent such as dichloromethane,dichloroethane, ethanol or isopropanol (or mixtures thereof) at ambientor elevated temperatures using conventional heating or heating bymicrowave irradiation providing piperidines of general formula 8 (Scheme2, step a). The alkyloxycarbonyl protecting group present in compounds 8can be removed, using e.g., 48% aqueous hydrogen bromide or 37% aqueoushydrochloric acid as reagent preferably at elevated temperatures toremove an ethyl carbamate or using trifluoroacetic acid or hydrochloricacid in a solvent like dichloromethane, dioxane or THF preferable atroom temperature to remove a tert-butyloxycarbonyl (BOC)-protectivegroup (see Protective Groups in Organic Synthesis, T. W. Greene and P.G. M. Wuts, 3^(rd) Edition, 1999, Wiley-Interscience), yieldingphenyl-piperidin-4-yl-amines of formula 9 (Scheme 2, step b). ReductiveN-alkylation of piperidines 9 with aldehydes 2 provides then access totarget structures Ia (Scheme 2, step c).

Alternatively, target structures of formula Ia can be accomplishedemploying an inverted reaction sequence. Reductive coupling of suitablyketone protected piperidines (for protecting groups see ProtectiveGroups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^(rd)Edition, 1999, Wiley-Interscience) such as1,4-dioxa-8-aza-spiro[4.5]decane (10) with aldehydes 2 providespiperidines 11 (Scheme 3, step a), which are subsequently deprotected tothe tertiary amine 12 (Scheme 3, step b). In the case of an acetal thisdeprotection step is preferentially conducted under acid catalysis(e.g., hydrochloric acid) in a solvent such as water under elevatedtemperatures. Finally, N-alkylation of benzyl-piperidinone 12 withaniline 6 under reductive reaction conditions affords target structuresIa (Scheme 3, step c). In contrast to the strategy outlined in Scheme 2,where the point of diversification is the aryl moiety, this syntheticroute is of particular interest if the variation of the benzyl moiety isaimed for in a rapid and parallel fashion.

The synthesis of target compounds of general formula I, particularlycompounds according to formula Ib is outlined in Scheme 4. ReductiveN-alkylation of suitably protected piperidines of formula I withaldehydes 2 in the presence of a reducing agent affords piperidines ofgeneral formula 3 (Scheme 4, step a). Removal of the preferentiallycarbamate protection group yields then the free 4-amino piperidines offormula 4 (Scheme 4, step b). Target structures of formula Ib areaccessible by nucleophilic replacement reaction of 4-amino-piperidinesof formula 4 and a variety of differentially substituted pyridines,quinolines, isoquinolines, naphthyridines and pyrazines of generalstructure 5 at room or elevated temperatures (Scheme 4, step c), wherebyX is a suitable leaving group such as fluorine, chlorine, bromine ormethyl sulfone. In order to enhance the rate of conversion heating mightbe applied, whereby conventional heating or microwave assisted heatingmight be employed using a suitable microwave irradiation apparatus. The4-amino-piperidines of formula 4 may thereby used either as a salt,e.g., hydrochloride or hydrobromide salt, or as the corresponding freeamine. Alternatively the nucleophilic displacement reaction can beconducted under basic conditions by using K₂CO₃, KOH, NaOCH₃, KOtert-Buor in particular by using NaH. Furthermore the reaction can be conductedin the presence of or without solvent (typically an aprotic polarsolvent such as DMF (N,N-dimethylformamide), DMAc (dimethylacetamide),NMP (N-methylpyrrolidon), ethylene glycol, acetonitrile or THF) and inthe presence of or without a tertiary amine base such as triethylamine,N-ethyl diisopropylamine or pyridine and in the presence with or withoutcopper(I) bromide or copper(I) iodide. The time for the reaction mayvary widely, depending on the many factors, notably the reactiontemperature and the nature of the reagents. However, a period of 0.5 hto several days will usually suffice to yield the piperidine derivativesof formula Ib.

The starting materials and some of the intermediates of generalstructure 5 (e.g., 2-chloro-pyridines, 2-chloro-quinolines or2-chloro-pyrazines) are known compounds and are commercially availableor can be prepared by numerous methods using conventional reactionprocedures generally known in the art. There is a plethora of referencesknown in the art teaching methods useful for the preparation ofaforementioned heterocyclic ring systems. The reader is referred to (a)A. R. Katritzky, Handbook of Heterocyclic Chemistry, 1985, PergamonPress Ltd, Oxford, United Kingdom (pyridine synthesis pp. 407-411;quinoline synthesis pp. 457-461; isoquinoline synthesis pp. 463-465;pyrazine synthesis pp. 432-433) and references cited therein, (b) T.Eicher and S. Hauptmann (translated by H. Suschitzky and J. Suschitzky),The Chemistry of Heterocycles, 1995, Georg Thieme Verlag, Stuttgart,Deutschland (pyridine synthesis pp. 295-305; quinoline synthesis pp.325-334; isoquinoline synthesis pp. 341-347; pyrazine synthesis pp.419-422) and references cited therein and (c) H. Krauch and W. Kunz,Reaktionen der organischen Chemie, 6, neubearbeitete Auflage, 1997,Huthig GmbH, Heidelberg, Deutschland (pyridine synthesis pp. 589-590;quinoline synthesis pp. 219-221; isoquinoline synthesis pp. 423-429;pyrazine synthesis pp. 578-580) and references cited therein.

Alternatively target structures Ib can be manufactured usingPd(0)-catalyzed amination reactions of 4-amino-piperidines 4 with 2-halopyridines, 2-halo-quinolines or 1-halo-isoquinolines of general formula13 (e.g., Buchwald-Hartwig coupling; see (a) J. P. Wolfe, S. Wagaw andS. L. Buchwald J. Am. Chem. Soc. 1996, 118, 7215-7216; (b) J. P. Wolfeand S. L. Buchwald Tetrahedron Lett. 1997, 38, 6359-6362; (c) J. P.Wolfe, S. Wagaw, J.-F. Marcoux and S. L. Buchwald Acc Chem. Res. 1998,31, 805-818; (d) B. H. Yang and S. L. Buchwald J. Organomet. Chem. 1999,576, 125-146; (e) J. F. Hartwig Angew. Chem. Int. Ed. 1998, 37,2046-2067). Thereby halo-substituted heterocylces 13 are reacted withprimary amines 4 under an inert atmosphere such as argon or nitrogen inthe presence of a palladium catalyst such astris(dibenzylideneacetone)dipalladium(0) (P d₂ (dba)₃) or palladium (II)acetate (Pd(COOCH₃)₂), a phosphine ligand like triphenylphosphine,rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (rac-BINAP) or(R)-(−)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine(Josiphos; see Q. Shen, S. Shekhar, J. P. Stambuli and J. F. HartwigAngew. Chem. Int. Ed. 2005, 44, 1371-1375) and a base such as Cs₂CO₃ orKOtert-Bu in a solvent like toluene, ethanol or water or mixturesthereof (Scheme 4, step c). Said C—N formation reaction may be conductedat room temperature or elevated temperatures, whereby heating might beachieved conventionally or by microwave irradiation (see alsoPalladium(0) Complexes in Organic Chemistry, in Organometallics inSynthesis (Ed. M. Schlosser), Chapter 4, 2^(nd) Edition, 2002, JohnWiley & Sons, Ltd, Chichester, UK).

If the nucleophilic substitution or Pd(0)-catalyzed amination reactionhas been conducted with starting materials which potentially can resultin regioisomeric coupling products such as asymmetrically substituted2,6-dichloro-pyridines or 1,3-dichloro-isoquinolines, the regiochemistryof target structures Ib was unambiguously established by means ofnuclear magnetic resonance spectroscopy employing 1D-NOE difference,2D-NOESY and/or ¹³C/¹HMBC experiments. In all cases reaction productswere successfully separated by conventional chromatographic methods.

Target structures of formula Ib can also be accomplished employing aninverted reaction sequence, namely by first coupling halo-substitutedheterocycles 13 with alkyloxycarbonyl protected amine 7 (Scheme 5, stepa). The protection group of piperidines 14 are then removed yielding thesecondary amines 15 (Scheme 5, step b), which undergo reductiveN-alkylation to target structures Ib (Scheme 5, step c). In contrast tothe strategy outlined in Scheme 4 where the point of diversification isthe heteroaryl moiety this synthetic route is of particular interest forthe rapid and parallel variation of the benzyl moiety.

Target compounds of formula Ia and Ib might also be manufactured bydirect alkylation of piperidines 9 and 15 with suitable halides,mesylates, tosylates or alcohols containing any other suitable leavinggroup of general structure 16 in a solvent such asN,N-dimethylformamide, dichloromethane, dichloroethane or acetone atambient or elevated temperatures using conventional heating or heatingby microwave irradiation with the addition of a suitable tertiary aminebase (e.g., triethylamine, N-ethyl diisopropylamine) or an inorganicbase (e.g., Cs₂CO₃, K₂CO₃; Scheme 6, step a) or by analogous alkylationreactions. Alternatively target structures of formula Ia and Ib might beaccessible by Mitsunobu reaction (D. L. Hughes, The Mitsunobu Reaction,in Organic Reactions, Volume 42, 1992, John Wiley & Sons, New York; pp.335-656) applying alcohols 17 activated by a mixture of a phosphine likea trialkylphosphine such as tributylphosphine ((n-Bu)₃P),triphenylphosphine (Ph₃P) and the like and a diazo-compound likediethyl-azodicarboxylate (DEAD), diisopropyl-azodicarboxylate (DIAD) ordi-tert-butyl-azodicarboxylate and the like in a solvent commonly usedfor such transfomations like tetrahydrofurane (THF), toluene,dichloromethane and the like (Scheme 6, step b). There is no particularrestriction on the nature of the solvent to be employed, provided thatit has no adverse effect on the reaction or the reagents involved andthat it can dissolve the reagents, at least to some extent. The reactioncan take place over a wide range of temperatures ranging from ambienttemperatures to the reflux temperature of the solvent employed. In caseof compounds of formula Ia, R^(a) has the meanings of R⁷ and R^(b),R^(c), R^(d) and R^(e) correspond to R⁸, R⁹, R¹⁰ and R¹¹, respectively.In case of compounds of formula Ib, R^(a) corresponds to R¹⁵ (B¹═CR^(b))or R¹⁸ (B¹═N), R^(b) can have the meanings of R⁴, R^(c) corresponds toR¹³ or R¹⁷ and R^(d) corresponds to R¹² or R¹⁶.

Compounds of formula Ib containing a cyano group can be furtherconverted to carboxamides under acidic or basic reaction conditions (forfurther reaction conditions see R. C. Larock, Comprehensive OrganicTransformations—A Guide to Functional Group Preparations, 1989, VCHPublishers Inc., New York; pp. 994). If the reaction is conducted underacidic conditions, preferentially hydrochloric acid or sulfuric acid areused at room temperature or elevated temperatures in a solvent such asdioxane or THF (tetrahydrofurane).

Compounds of formula Ib containing an alkyl ester group, preferentiallya methyl ester group, can be further transformed to carboxamides underbasic reaction conditions (for further reaction conditions see R. C.Larock, Comprehensive Organic Transformations—A Guide to FunctionalGroup Preparations, 1989, VCH Publishers Inc., New York; pp. 987-988),preferentially using ammonium hydroxide in the presence of potassiumcyanide at room temperature or elevated temperatures in a solvent suchas DMF (N,N-dimethylformamide) or DMAc (dimethylacetamide). In order toenhance the rate of conversion heating might be applied, wherebyconventional heating or microwave assisted heating might be employedusing a suitable microwave irradiation apparatus.

Compounds of formula Ib containing an alkyl ester group, preferentiallya methyl ester group, can be further converted to carboxylic acids underbasic reaction conditions (for further reaction conditions see R. C.Larock, Comprehensive Organic Transformations—A Guide to FunctionalGroup Preparations, 1989, VCH Publishers Inc., New York; pp. 981-985),preferentially using potassium or sodium hydroxide at room temperatureor elevated temperatures in a solvent such as methanol, dioxane, THF(tetrahydrofurane), DMF (N,N-dimethylformamide) or DMAc(dimethylacetamide) or mixtures thereof. In order to enhance the rate ofconversion heating might be applied, whereby conventional heating ormicrowave assisted heating might be employed using a suitable microwaveirradiation apparatus.

Compounds of formula Ib containing a carboxylic acid function can befurther transformed to amides by reaction with primary or secondaryamines (for further reaction conditions see R. C. Larock, ComprehensiveOrganic Transformations—A Guide to Functional Group Preparations, 1989,VCH Publishers Inc., New York; pp. 972-976). The coupling of carboxylicacids with amines is widely described in literature and the proceduresare known to those in the art (see also R. C. Larock, OrganicTransformations: A Guide to Functional Group Preparations, 2^(nd)Edition, 1999, John Wiley & Sons, New York). Preferentially, nicotinicacids of general structure Ib can conveniently be transformed to therespective amide through coupling with a primary or secondary amineemploying a coupling agent. Suitable coupling agents for the reaction ofcarboxylic acids with amines are for example N,N′-carbonyldiimidazole(CDI), N,N′-dicyclohexylcarbodiimide (DCC),1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyl-uronium tetrafluoroborate(TBTU) and the like. Preferred coupling agents are1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU) orO-benzotriazol-1-yl-N,N,N′-tetramethyl-uronium tetrafluoroborate (TBTU).Solvents commonly used for such kind of reactions are DMF(N,N-dimethylformamide), DMAc (dimethylacetamide), DCM(dichloromethane), dioxane, THF (tetrahydrofurane) and the like in thepresence of or without a tertiary amine base such as N-ethyldiisopropylamine, triethylamine or pyridine. The reaction can take placeover a wide range of temperatures from ambient temperature to the refluxtemperature of the solvent applied. The time for the reaction may alsovary widely, depending on the many factors, notably the reactiontemperature and the nature of the reagents. However, a period of 0.5 hto several days will usually suffice to yield the amide derivatives offormula Ib.

Synthesis of Aldehyde Intermediates

The requisite aldehyde partners are either commercially available or canbe derived by alkylation with alkyl halides, alkyl mesylates, alkyltosylates or alcohols containing any other suitable leaving group in apolar solvent such as DMF (N,N-dimethylformamide) or acetone and asuitable base (e.g., Cs₂CO₃, K₂CO₃) at room temperature or elevatedtemperatures, by Mitsunobu reaction with alcohols activated by a mixtureof triphenylphosphine and diethylazadicarboxylate, or by analogousalkylation of the phenolic carboxylic esters or acids of formula 18(Scheme 7, step a). Reduction of the esters of formula 19 by a suitablereducing agent (e.g., diisobutylaluminium hydride at low temperature,with LiAlH₄ at elevated or ambient temperature) in a solvent such as THF(tetrahydrofurane) provides the corresponding benzylalcohols of formula20 (Scheme 7, step b). These can then be oxidized to the aldehydes offormula 21, preferably with activated MnO₂ as oxidant in dichloromethane(Scheme 7, step c).

Alternatively the introduction of the side-chain can be accomplished bydirect alkylation (sequential for unsymmetrical compounds) of thephenolic benzaldehydes of formula 22 providing the desired compounds offormula 21 directly (Scheme 7, step d).

A further well-established route towards the synthesis ofbenzylaldehydes of formula 24 consists in the reduction of thecorresponding benzonitriles of formula 23 by a suitable reducing agentsuch as diisobutylaluminium hydride at low temperature in a non-proticpolar solvent (e.g., THF; Scheme 7, step e).

Additional syntheses of aldehydes of formula II are described in theexamples.

As described hereinbefore, it has been found that the compounds offormula I possess pharmaceutical activity, in particular they aremodulators of somatostatin receptor activity. More particularly, thecompounds of the present invention have been found to be antagonists ofthe somatostatin receptor subtype 5 (SSTR5).

The following tests were carried out in order to determine the activityof the compounds of formula I.

A CHO cell line stably transfected with a plasmid encoding the humansubtype 5 somatostatin receptor (GenBank accession number D16827) wasobtained from Euroscreen. Cells were cultured and used for binding andfunctional assays.

Membranes of these cells were prepared by sonication in the presence ofprotease inhibitors and subsequent fractionating centrifugation. Theprotein concentration in the membrane preparation was determined using acommercial kit (BCA kit, Pierce, USA). Membranes were stored at −80° C.until use. After thawing, membranes were diluted in assay buffer (50 mMTris-HCl at pH 7.4, 5 mM MgCl₂ and 0.20% BSA) and subjected to douncehomogenization.

For binding studies, 0.1 mL membrane suspension, corresponding to app.6×10⁻¹⁵ mol receptor, was incubated for 1 h at room temperature with0.05 nM ¹²⁵I-labeled tracer (1-Tyr somatostatin-14, Perkin-Elmer) andeither test compounds in varying concentrations or, for thedetermination of non-specific binding, 0.001 mM non-labeledsomatostatin-14. The incubation was stopped by filtration through GFIBglassfiber filters and washing with ice-cold wash buffer (50 mM Tris-HClat pH 7.4). The bound radioactivity was measured after application of ascintillation cocktail (Microscint 40) and expressed as disintegrationsper minute (dpm).

The receptor concentration was determined in a prior saturationexperiment where a fixed, arbitrary amount of membranes was incubatedwith a concentration range of radio-labeled tracer. This allowsestimating the total number of specific binding sites per amount ofprotein (i.e., B_(max)), typically between 1 and 5 μmol/mg.

The concentration of the test compound required to result in halfmaximal inhibition of binding of the radio-labeled tracer (IC₅₀) wasestimated from a concentration-versus-dpm graph. The binding affinity(K_(i)) was calculated from the IC₅₀ by applying the Cheng-Prussoffequation for single binding sites.

For functional experiments, 50'000 cells were incubated in Krebs RingerHEPES buffer (115 mM NaCl, 4.7 mM KCl, 2.56 mM CaCl₂, 1.2 mM KH₂PO₄, 1.2mM MgSO₄, 20 mM NaHCO₃ and 16 mM HEPES, adjusted to pH 7.4) supplementedwith 1 mM IBMX and 0.1% BSA, then stimulated with 0.004 mM forskolin.Simultaneously with forskolin, test compounds in varying concentrationswere applied. Cells were then incubated for 20 minutes at 37° C. and 5%CO₂. Subsequently, cells were lysed and cAMP concentration measuredusing a fluorescence-based commercial kit according to the manufacturer(HitHunter cAMP, DiscoverX).

The concentration of the test compound to induce a half maximal effect(i.e., EC₅₀) as well as the efficacy as compared to 0.15 nMsomatostatin-14 were determined from concentration-versus-fluorescence(arbitrary units) graphs. For the determination of potential antagonism,0.15 nM somatostatin-14 was applied together with the test compounds andthe concentration of the test compounds to half maximally reverse theeffect of somatostatin-14 (i.e., IC₅₀) were deduced fromconcentration-versus-fluorescence graphs.

The compounds of the present invention exhibit K_(i) values of 0.1 nM to10 μM, preferably K_(i) values of 1 nM to 500 nM and more preferably 0.1nM to 100 nM for human subtype 5 somatostatin receptor. The followingtable shows measured values for selected compounds of the presentinvention.

SSTR5 K_(i) (nmol/l) Example 24 789 Example 103 7 Example 205 86

The compounds of formula I and their pharmaceutically acceptable saltsand esters can be used as medicaments, e.g., in the form ofpharmaceutical preparations for enteral, parenteral or topicaladministration. They can be administered, for example, perorally, e.g.,in the form of tablets, coated tablets, dragées, hard and soft gelatinecapsules, solutions, emulsions or suspensions, rectally, e.g., in theform of suppositories, parenterally, e.g., in the form of injectionsolutions or infusion solutions, or topically, e.g., in the form ofointments, creams or oils.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and their pharmaceuticallyacceptable, into a galenical administration form together with suitable,non-toxic, inert, therapeutically compatible solid or liquid carriermaterials and, if desired, usual pharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragées and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers are,however, required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavour-improving agents, salts forvarying the osmotic pressure, buffer substances, solubilizers, colorantsand masking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 mg to about 1000 mg,especially about 1 mg to about 100 mg, comes into consideration.Depending on the dosage it is convenient to administer the daily dosagein several dosage units.

The pharmaceutical preparations conveniently contain about 0.1-500 mg,preferably 0.5-100 mg, of a compound of formula I.

The present invention will be further explained by reference to thefollowing illustrative examples. They are, however, not intended tolimit its scope in any manner.

EXAMPLES Abbreviations

Ar=argon, DMAc=dimethylacetamide, DMF=N,N-dimethylformamide, DMSOdimethyl sulfoxide, E1=electron impact (ionization), ESI=electron sprayionisation, HATU1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate, HPLC=high performance liquid chromatography, HyfloSuper Cel®=filtration aid (Fluka), ISN=ion spray negative (mode),ISP=ion spray positive (mode), Josiphos ligand ═(R) —(−)-1-[(S)-2-(dicyclohexyl-phosphino)-ferrocenyl]ethyl-di-tert-butylphosphine,NMP=N-methylpyrrolidon, NMR=nuclear magnetic resonance, MPLC mediumpressure liquid chromatography, MS=mass spectrum, P=protecting group,R=any group, rt=room temperature, THF=tetrahydrofuran, X=halogen, Y=anygroup including heteroatoms and halides.

Example 14-[1-(3-Ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-benzonitrile

Step 1: [1-(3-Ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-carbamic acidtert-butyl ester

A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (10.0 g, 50.0mmol, 1.0 equiv; commercially available),3-ethoxy-4-methoxy-benzaldehyde (10.8 g, 60.0 mmol, 1.2 equiv;commercially available) and acetic acid (11.4 mL, 12.01 g, 200.0 mmol,4.0 equiv) in ethanol (40 mL) was heated by microwave irradiation to100° C. for 5 min. Sodium cyanoborohydride (6.27 g, 100.0 mmol, 2.0equiv), dissolved in ethanol (20 mL), was added and the reaction mixtureheated by microwave irradiation to 100° C. for an additional time periodof 5 min. The solvent was removed under reduced pressure and the crudereaction product extracted from a solution of 1 M NaOH (200 mL) withethyl acetate (3×100 mL). The combined organic phases were dried overMgSO₄, concentrated by evaporation under reduced pressure and the crudematerial purified with column chromatography on silica eluting withethyl acetate to yield 9.71 g (53%) of the title compound as a whitesolid. MS (ISP): 365.3 [M+H]⁺.

Step 2: 1-(3-Ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (IntermediateA1)

A solution of [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-carbamicacid tert-butyl ester (9.71 g, 26.64 mmol) in ethanol (50 mL) and 4 MHCl in dioxane (75 mL) was stirred at rt for 2 h. The hydrochloric acidwas removed under reduced pressure and the crude reaction productextracted from a solution of 1 M NaOH (200 mL) with ethyl acetate (3×100mL). The combined organic phases were dried over MgSO₄ and concentratedby evaporation under reduced pressure yielding 4.69 g (89%) of a whitesolid. The crude material was directly used in the following reactionstep. MS (ESI): 265.0 [M+H]⁺.

Step 3:4-[1-(3-Ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-benzonitrile

A solution of 4-fluoro-benzonitrile (36.3 mg, 0.30 mmol, 1.0 equiv;commercially available) and1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (95.2 mg, 0.36 mmol,1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwaveirradiation to 210° C. for 3 h. Removal of the solvent under reducedpressure and purification by preparative HPLC on reversed phase elutingwith a gradient of acetonitrile/water provided 17.8 mg (16%) of thetitle compound. MS (ISP): 366.4 [M+H]⁺.

Example 24-[1-(4-Chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-benzonitrile

Step 1: [1-(4-Chloro-3-ethoxy-benzyl)-piperidin-4-yl]-carbamic acidtert-butyl ester

A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (5.0 g, 25.0mmol, 1.0 equiv; commercially available), 4-chloro-3-ethoxy-benzaldehyde(5.54 g, 30.0 mmol, 1.2 equiv; intermediate E2, vide infra) and aceticacid (5.7 mL, 6.01 g, 100.0 mmol, 4.0 equiv) in ethanol (25 mL) washeated by microwave irradiation to 100° C. for 5 min. Sodiumcyanoborohydride (3.14 g, 50.0 mmol, 2.0 equiv), dissolved in ethanol(10 mL), was added and the reaction mixture heated by microwaveirradiation to 100° C. for an additional time period of 10 min. Thesolvent was removed under reduced pressure and the crude reactionproduct extracted from a solution of 1 M NaOH (100 mL) with ethylacetate (3×100 mL). The combined organic phases were dried over MgSO₄,concentrated by evaporation under reduced pressure and the crudematerial purified by silica column chromatography using a MPLC system(CombiFlash Companion, Isco Inc.) eluting with a gradient ofheptane/ethyl acetate providing 3.91 g (42%) of the title compound. MS(ISP): 369.0 [M+H]⁺.Step 2: 1-(4-Chloro-3-ethoxy-benzyl)-piperidin-4-ylamine (IntermediateA2)

A solution of [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-carbamicacid tert-butyl ester (0.78 g, 2.12 mmol) in ethanol (10 mL) and 4 M HCl(15 mL) was stirred at rt for 2 h. The hydrochloric acid was removedunder reduced pressure and the crude reaction product extracted from asolution of 1 M NaOH (50 mL) with ethyl acetate (3×50 mL). The combinedorganic phases were dried over MgSO₄ and concentrated by evaporationunder reduced pressure yielding 0.32 g (57%) of a white solid. The crudematerial was directly used in the following reaction step. MS (ISP):269.0 [M+H]⁺.

Step 3:4-[1-(4-Chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-benzonitrile

A solution of 4-fluoro-benzonitrile (36.3 mg, 0.30 mmol, 1.0 equiv;commercially available) and1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamine (96.8 mg, 0.36 mmol,1.2 equiv; intermediate A2) in DMAc (2 mL) was heated by microwaveirradiation to 210° C. for 3 h. Removal of the solvent under reducedpressure and purification by preparative HPLC on reversed phase elutingwith a gradient of acetonitrile/water provided 10.9 mg (10%) of thetitle compound. MS (ISP): 370.1 [M+H]⁺.

Example 3N-{3-[1-(4-Chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-phenyl}-acetamide

Step 1: 4-(3-Acetylamino-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester

A mixture of N-(3-amino-phenyl)-acetamide (0.19 g, 1.25 mmol, 1.0 equiv;commercially available) and 4-oxo-piperidine-1-carboxylic acidtert-butyl ester (0.3 g, 1.50 mmol, 1.2 equiv; commercially available)in isopropanol (2 mL) was heated by microwave irradiation to 120° C. for20 min. Sodium cyanoborohydride (0.16 g, 2.50 mmol, 2.0 equiv),dissolved in isopropanol (2 mL), was added and the reaction mixtureheated by microwave irradiation to 120° C. for an additional time periodof 20 min. The crude reaction material was purified by silica columnchromatography eluting with heptane/ethyl acetate (1:2) providing 0.21 g(49%) of the title compound. MS (ISP): 334.3 [M+H]⁺.

Step 2: N-[3-(Piperidin-4-ylamino)-phenyl]-acetamide dihydrochloride(Intermediate B1)

A solution of 4-(3-acetylamino-phenylamino)-piperidine-1-carboxylic acidtert-butyl ester (0.21 g, 0.63 mmol) in 4 M HCl in dioxane (10 mL) wasstirred at rt for 2 h. The solvent was removed under reduced pressureand the crude product used in the consecutive step without furtherpurification assuming quantitative deprotection and formation of thedihydrochloride salt. MS (ISP): 234.4 [M+H]⁺.

Step 3:N-{3-[1-(4-Chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-phenyl}-acetamide

To a solution of N-[3-(piperidin-4-ylamino)-phenyl]-acetamidedihydrochloride (61.2 mg, 0.2 mmol, 1.0 equiv; intermediate B1), aceticacid (60.1 mg, 1.0 mmol, 5.0 equiv) and triethylamine (40.5 mg, 0.4mmol, 2.0 equiv) in ethanol (1 mL) was added4-chloro-3-ethoxy-benzaldehyde (46.1 mg, 0.25 mmol, 1.25 equiv;intermediate E2, vide infra) and the mixture stirred at 50° C. After 1h, sodium cyanoborohydride (15.1 mg, 0.24 mmol, 1.2 equiv), dissolved inethanol (1 mL), was added and the mixture stirred at 50° C. over night.Removal of the solvent under reduced pressure and purification bypreparative HPLC on reversed phase eluting with a gradient ofacetonitrile/water provided 10.0 mg (12%) of the title compound. MS(ISP): 402.3 [M+H]⁺.

Example 4N-{3-[1-(3,5-Diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-phenyl}-acetamide

To a solution of N-[3-(piperidin-4-ylamino)-phenyl]-acetamidedihydrochloride (61.2 mg, 0.2 mmol, 1.0 equiv; intermediate B1), aceticacid (60.1 mg, 1.0 mmol, 5.0 equiv) and triethylamine (40.5 mg, 0.4mmol, 2.0 equiv) in ethanol (1 mL) was added3,5-diethoxy-4-fluoro-benzaldehyde (53.1 mg, 0.25 mmol, 1.25 equiv;intermediate E5, vide infra) and the mixture stirred at 50° C. After 1h, sodium cyanoborohydride (15.1 mg, 0.24 mmol, 1.2 equiv), dissolved inethanol (1 mL), was added and the mixture stirred at 50° C. over night.Removal of the solvent under reduced pressure and purification bypreparative HPLC on reversed phase eluting with a gradient ofacetonitrile/water provided 19.9 mg (23%) of the title compound. MS(ISP): 430.4 [M+H]⁺.

Example 5[1-(3-Ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(4-ethyl-phenyl)-amine

Step 1: 1-(3-Ethoxy-4-methoxy-benzyl)-piperidin-4-one (Intermediate C1)

A mixture of 1,4-dioxa-8-aza-spiro[4.5]decane (9.33 g, 65.16 mmol, 1.0equiv; commercially available) and 3-ethoxy-4-methoxy-benzaldehyde(14.09 g, 78.19 mmol, 1.2 equiv; commercially available) in ethanol (50mL) and acetic acid (5 mL) was heated to 50° C. for 1 h. Sodiumcyanoborohydride (4.91 g, 78.19 mmol, 1.2 equiv), dissolved in ethanol(20 mL), was added and the reaction mixture heated to 50° C. After 2 h,a solution of 37% HCl in water (100 mL) was added and the reactionmixture heated to 100° C. for 3 h. The solvent was removed under reducedpressure and the crude reaction product extracted from a solution of 1 MNaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phaseswere dried over MgSO₄, concentrated by evaporation under reducedpressure and the crude material purified with column chromatography onsilica eluting with a gradient of heptane/ethyl acetate (1:3)→ethylacetate to provide 11.23 g (59%) of the title compound. ¹H NMR (300 MHz,CDCl₃): δ1.46 (t, J=6.9 Hz, 3H), 2.41-2.44 (m, 4H), 2.69-2.73 (m, 4H),3.53 (s, 2H), 3.87 (s, 3H), 4.11 (q, J=6.9 Hz, 2H), 6.80-6.86 (m, 2H),6.94 (s, 1H). ¹³C NMR (75 MHz, CDCl₃): δ14.49, 41.16, 52.71, 55.90,61.00, 64.50, 111.43, 113.71, 121.04, 130.77, 148.17, 148.68, 208.71. MS(ISP): 263.9 [M+H]⁺.

Step 2:[1-(3-Ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(4-ethyl-phenyl)-amine

A solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-one (94.8 mg,0.36 mmol, 1.2 equiv; intermediate C1) and 4-ethyl-phenylamine (36.4 mg,0.30 mmol, 1.0 equiv; commercially available) in ethanol (2 mL) andacetic acid (0.38 mL) was heated to 85° C. After 2 h, sodiumcyanoborohydride (22.6 mg, 0.36 mmol, 1.2 equiv), dissolved in ethanol(1 mL), was added and the mixture stirred at 85° C. over night. Removalof the solvent under reduced pressure and purification by preparativeHPLC on reversed phase eluting with a gradient of acetonitrile/waterprovided 17.2 mg (16%) of the title compound. MS (ISP): 369.4 [M+H]⁺.

Examples 6 to 10

According to the procedure described for the synthesis of example 5/step2 further phenyl derivatives have been synthesized from1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-one (intermediate C1) and therespective aniline intermediate as indicated in Table 1. The results arecompiled in Table 1 and comprise example 6 to example 10.

TABLE 1 ISP [M + H]⁺ No MW Compound Name Starting Materials found 6447.60 C-{4-[1-(3-Ethoxy-4- 1-(3-ethoxy-4-methoxy- 448.1methoxy-benzyl)- benzyl)-piperidin-4-one piperidin-4-ylamino]-(intermediate C1) and C-(4- phenyl}-N-methyl- amino-phenyl)-N-methyl-methanesulfonamide methanesulfonamide (commercially available) 7 430.57(2,2-dioxo-2,3-dihydro- 1-(3-ethoxy-4-methoxy- 431.31H-2λ⁶-benzo[c]thiophen- benzyl)-piperidin-4-one 5-yl)-[1-(3-ethoxy-4-(intermediate C1) and 2,2- methoxy-benzyl)- dioxo-2,3-dihydro-1H-2λ⁶-piperidin-4-yl]-amine benzo[c]thiophen-5-ylamine (commerciallyavailable) 8 384.48 4-[1-(3-ethoxy-4- 1-(3-ethoxy-4-methoxy- 385.4methoxy-benzyl)- benzyl)-piperidin-4-one piperidin-4-ylamino]-(intermediate C1) and 4- benzoic acid amino-benzoic acid (commerciallyavailable) 9 500.62 4-[1-(3-ethoxy-4- 1-(3-ethoxy-4-methoxy- 501.2methoxy-benzyl)- benzyl)-piperidin-4-one piperidin-4-ylamino]-N-(intermediate C1) and 4- (5-methyl-isoxazol-3-yl)- amino-N-(5-methyl-benzenesulfonamide isoxazol-3-yl)- benzenesulfonamide (commerciallyavailable) 10 433.57 N-{4-[1-(3-ethoxy-4- 1-(3-ethoxy-4-methoxy- 434.4methoxy-benzyl)- benzyl)-piperidin-4-one piperidin-4-ylamino]-(intermediate C1) and N-(4- phenyl}- amino-phenyl)- methanesulfonamidemethanesulfonamide (commercially available)

Example 11[5-(1H-Benzoimidazol-2-yl)-pyridin-2-yl]-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine

A solution of 2-(6-chloro-pyridin-3-yl)-1H-benzoimidazole (23.0 mg, 0.10mmol, 1.0 equiv; commercially available) and1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol,1.5 equiv; intermediate A1) in ethylene glycol (2 mL) was heated bymicrowave irradiation to 220° C. for 20 min. Removal of the solventunder reduced pressure and purification by preparative HPLC on reversedphase eluting with a gradient of acetonitrile/water provided 4.0 mg (9%)of the title compound. MS (ISP): 456.6 [M−H]⁻.

Example 12(7-Chloro-4-methoxymethyl-quinolin-2-yl)-[1-(3-ethoxy-4-methoxyl-benzyl)-piperidin-4-yl]-amine

Step 1: 2,7-Dichloro-4-methoxymethyl-quinoline

To a solution of 4-bromomethyl-7-chloro-quinolin-2-ol (500.0 mg, 1.84mmol, 1.0 equiv; [CAS RN 23976-53-6]; prepared according to R. J.Chudgar and K. N. Trivedi J. Ind. Chem. Soc. 1969, 46, 537-540) andcollidine (333.5 mg, 2.75 mmol, 1.5 equiv) in acetonitril (15 mL) wasadded phosphorus oxychloride (1.0 mL, 1.69 g, 11.0 mmol, 6.0 equiv) andthe reaction mixture heated to 110° C. over night. The reaction mixturewas poured on ice, the pH adjusted to 9 by addition of a sat. solutionof Na₂CO₃ (100 mL) and the solution extracted with ethyl acetate (3×50mL). The organic phase was dried over Na₂SO₄ and concentrated byevaporation under reduced pressure yielding 0.43 g of a mixture of4-bromomethyl-2,7-dichloro-quinoline and2,7-dichloro-4-chloromethyl-quinoline according to ¹H NMR, which wasused directly in the consecutive step without further purification. Themixture was dissolved in MeOH (20 mL) and sodium methoxide (99.4 mg,1.84 mmol, 1.0 equiv) was added. After heating to 60° C. for 8 h, thesolvent was removed under reduced pressure and the crude materialpurified with silica column chromatography eluting with hexane/diethylether (10:1) to provide 0.17 g (38%) of the title compound. ¹H NMR (250MHz, CDCl₃): δ3.54 (s, 3H), 4.87 (s, 2H), 7.48 (s, 1H), 7.53 (dd, J=9.0Hz, J=2.1 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 8.03 (d, J=2.1 Hz, 1H). MS(EI): 242 [M]⁺.

Step 2:(7-Chloro-4-methoxymethyl-quinolin-2-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine

A solution of 2,7-dichloro-4-methoxymethyl-quinoline (36.3 mg, 0.15mmol, 1.0 equiv) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine(47.6 mg, 0.18 mmol, 1.5 equiv; intermediate A1) in NMP (2 mL) washeated by microwave irradiation to 200° C. for 30 min. Removal of thesolvent under reduced pressure and purification by preparative HPLC onreversed phase eluting with a gradient of acetonitrile/water provided9.6 mg (14%) of the title compound. MS (ISP): 470.4 [M+H]⁺.

Example 13[1-(3-Ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(6-fluoro-quinolin-2-yl)-amine

Step 1: 2-Chloro-6-fluoro-quinoline (Intermediate D1) [CAS RN77119-53-0]

The title compound was prepared according to S. R. Inglis, C. Stojkoski,K. M. Branson, J. F. Cawthray, D. Fritz, E. Wiadrowski, S. M. Pyke andG. W. Booker J. Med. Chem. 2004, 47, 5405-5417.

Step 2:[1-(3-Ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(6-fluoro-quinolin-2-yl)-amine

A solution of 2-chloro-6-fluoro-quinoline (27.2 mg, 0.15 mmol, 1.0equiv; intermediate D1) and1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol,1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwaveirradiation to 220° C. for 1 h. Removal of the solvent under reducedpressure and purification by preparative HPLC on reversed phase elutingwith a gradient of acetonitrile/water provided 2.2 mg (4%) of the titlecompound. MS (ISP): 410.4 [M+H]⁺.

Example 146-[1-(3-Ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-nicotinonitrile

Method A:

A solution of 6-chloro-nicotinonitrile (20.8 mg, 0.15 mmol, 1.0 equiv;commercially available) and1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol,1.2 equiv; intermediate A1) in DMAc (1.5 mL) was heated by microwaveirradiation to 180° C. for 10 min. Removal of the solvent under reducedpressure and purification by preparative HPLC on reversed phase elutingwith a gradient of acetonitrile/water provided 2.2 mg (4%) of the titlecompound. MS (ISP): 367.3 [M+H]⁺.

Example 15[1-(3-Ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine

Method B:

To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7mg, 0.15 mmol, 1.2 equiv; intermediate A1) in dry DMF (1.5 mL) under Arwas added sodium hydride (6.6 mg, 0.15 mmol, 1.2 equiv; 55% free-flowingpowder moistened with oil) and the reaction mixture stirred at rt. After2 h, 2-chloro-5-trifluoromethyl-pyridine (22.7 mg, 0.125 mmol, 1.0equiv; commercially available) was added and the mixture heated bymicrowave irradiation to 160° C. for 15 min. Removal of the solventunder reduced pressure and purification by preparative HPLC on reversedphase eluting with a gradient of acetonitrile/water provided 4.8 mg (8%)of the title compound. MS (ISP): 410.3 [M+H]⁺.

Example 16(6-Chloro-pyridin-2-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine

Method C:

To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7mg, 0.15 mmol, 1.2 equiv; intermediate A1) in dry DMF (1.5 mL) under Arwas added sodium hydride (6.6 mg, 0.15 mmol, 1.2 equiv; 55% free-flowingpowder moistened with oil) and the reaction mixture stirred at rt. After2 h, 2,6-dichloro-pyridine (18.5 mg, 0.125 mmol, 1.0 equiv; commerciallyavailable) was added and the mixture heated by microwave irradiation to140° C. for 1 h. Removal of the solvent under reduced pressure andpurification by preparative HPLC on reversed phase eluting with agradient of acetonitrile/water provided 1.1 mg (2%) of the titlecompound. MS (ISP): 376.3 [M+H]⁺.

Example 176-[1-(3-Ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-nicotinic acidethyl ester

Method D:

To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7mg, 0.15 mmol, 1.0 equiv; intermediate A1) in dry DMF (1.5 mL) under Arwas added sodium hydride (6.6 mg, 0.15 mmol, 1.0 equiv; 55% free-flowingpowder moistened with oil) and the reaction mixture stirred at rt. After2 h, 6-chloro-nicotinic acid ethyl ester (46.4 mg, 0.25 mmol, 1.67equiv; commercially available) was added and the mixture heated bymicrowave irradiation to 220° C. for 15 min. Removal of the solventunder reduced pressure and purification by preparative HPLC on reversedphase eluting with a gradient of acetonitrile/water provided 10.9 mg(18%) of the title compound. MS (ISP): 414.4 [M+H]⁺.

Examples 18 to 27

According to the procedure described for the synthesis of example 14(Method A), example 15 (Method B), example 16 (Method C) and example 17(Method D) further pyridine, quinoline and naphthyridine derivativeshave been synthesized from1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (intermediate A1) andthe respective pyridine, quinoline and naphthyridine intermediate asindicated in Table 2. The results are compiled in Table 2 and compriseexample 18 to example 27.

TABLE 2 ISP [M + H]⁺ No MW Compound Name Preparation Starting Materialsfound 18 399.49 6-[1-(3-ethoxy-4- Method B 1-(3-ethoxy-4-methoxy- 400.4methoxy-benzyl)- benzyl)-piperidin-4- piperidin-4-ylamino]- ylamine(intermediate nicotinic acid methyl A1) and 6-chloro- ester nicotinicacid methyl ester (commercially available) 19 386.45 [1-(3-ethoxy-4-Method A 1-(3-ethoxy-4-methoxy- 387.3 methoxy-benzyl)-benzyl)-piperidin-4- piperidin-4-yl]-(5- ylamine (intermediatenitro-pyridin-2-yl)- A1) and 2-chloro-5- amine nitro-pyridine(commercially available) 20 420.36 (5-bromo-pyridin-2- Method D1-(3-ethoxy-4-methoxy- 422.2 yl)-[1-(3-ethoxy-4- benzyl)-piperidin-4-methoxy-benzyl)- ylamine (intermediate piperidin-4-yl]-amine A1) and5-bromo-2- chloro-pyridine (commercially available) 21 400.48[1-(3-ethoxy-4- Method C 1-(3-ethoxy-4-methoxy- 401.4 methoxy-benzyl)-benzyl)-piperidin-4- piperidin-4-yl]-(6- ylamine (intermediatemethyl-5-nitro- A1) and 6-chloro-2- pyridin-2-yl)-aminemethyl-3-nitro-pyridine (commercially available) 22 401.47N⁶-[1-(3-ethoxy-4- Method C 1-(3-ethoxy-4-methoxy- 402.4methoxy-benzyl)- benzyl)-piperidin-4- piperidin-4-yl]-3- ylamine(intermediate nitro-pyridine-2,6- A1) and 6-chloro-3- diaminenitro-pyridin-2-ylamine (commercially available) 23 433.942-chloro-6-[1-(3- Method C 1-(3-ethoxy-4-methoxy- 434.3ethoxy-4-methoxy- benzyl)-piperidin-4- benzyl)-piperidin-4- ylamine(intermediate ylamino]-isonicotinic A1) and 2,6-dichloro- acid methylester isonicotinic acid methyl ester (commercially available) 24 456.592-[1-(3-ethoxy-4- Method C 1-(3-ethoxy-4-methoxy- 457.4 methoxy-benzyl)benzyl)-piperidin-4- piperidin-4-ylamino]- ylamine (intermediate6-methyl-5-phenyl- A1) and 2-chloro-6- nicotinonitrile methyl-5-phenyl-nicotinonitrile (commercially available) 25 418.90 2-chloro-6-[1-(3-Method C 1-(3-ethoxy-4-methoxy- 419.2 ethoxy-4-methoxy-benzyl)-piperidin-4- benzyl)-piperidin-4- ylamine (intermediateylamino]-5-fluoro- A1) and 2,6-dichloro-5- nicotinonitrilefluoro-nicotinonitrile (commercially available) 26 391.51[1-(3-ethoxy-4- Method D 1-(3-ethoxy-4-methoxy- 392.2 methoxy-benzyl)-benzyl)-piperidin-4- piperidin-4-yl]- ylamine (intermediatequinolin-2-yl-amine A1) and 2-chloro- quinoline (commercially available)27 406.53 [1-(3-ethoxy-4- Method C 1-(3-ethoxy-4-methoxy- 407.4methoxy-benzyl)- benzyl)-piperidin-4- piperidine-4-yl]-(5- ylamine(intermediate methyl- A1) and 2-chloro-5- [1,6]naphthyridin-2- methyl-yl)-amine [1,6]naphthyridine (commercially available)

Example 28{2-Chloro-6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-pyridin-4-yl}-methanol

Method E:

A solution of (2,6-dichloro-pyridin-4-yl)-methanol (44.5 mg, 0.25 mmol,1.25 equiv; commercially available) and1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamine (53.8 mg, 0.20 mmol,1.2 equiv; intermediate A2) in DMF (2.0 mL) was heated by microwaveirradiation to 220° C. for 1 h. Removal of the solvent under reducedpressure and purification by preparative HPLC on reversed phase elutingwith a gradient of acetonitrile/water provided 3.2 mg (4%) of the titlecompound. MS (ISP): 410.3 [M+H]⁺.

The pyridine intermediate D2 was prepared following literatureprecedents.

Synthesis of Pyridine Intermediate D2 to be Used in Table 3

Intermediate D2 2,6-Dichloro-4-methoxymethyl-pyridine [CAS RN221093-39-6]

The title compound was prepared according to WO 99/12907 (Dainippon Inkand Chemicals, Inc.).

Examples 29 to 37

According to the procedure described for the synthesis of example 15(Method B), example 16 (Method C) and example 28 (Method E) furtherpyridine, quinoline and naphthyridine derivatives have been synthesizedfrom 1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamine (intermediate A2)and the respective pyridine, quinoline and naphthyridine intermediate asindicated in Table 3. The results are compiled in Table 3 and compriseexample 29 to example 37.

TABLE 3 ISP [M + H]⁺ No MW Compound Name Preparation Starting Materialsfound 29 403.91 6-[1-(4-chloro-3- Method B 1-(4-chloro-3-ethoxy- 404.4ethoxy-benzyl)- benzyl)-piperidin-4-ylamine piperidin-4- (intermediateA2) and 6- ylamino]-nicotinic chloro-nicotinic acid methyl acid methylester ester (commercially available) 30 413.87 [1-(4-chloro-3- Method C1-(4-chloro-3-ethoxy- 414.3 ethoxy-benzyl)- benzyl)-piperidin-4-ylaminepiperidin-4-yl]-(5- (intermediate A2) and 2- trifluoromethyl-chloro-5-trifluoromethyl- pyridin-2-yl)- pyridine (commercially amineavailable) 31 413.87 [1-(4-chloro-3- Method C 1-(4-chloro-3-ethoxy-414.3 ethoxy-benzyl)- benzyl)-piperidin-4-ylamine piperidin-4-yl]-(3-(intermediate A2) and 2- trifluoromethyl- chloro-3-trifluoromethyl-pyridin-2-yl)- pyridine (commercially amine available) 32 404.90[1-(4-chloro-3- Method C 1-(4-chloro-3-ethoxy- 405.3 ethoxy-benzyl)-benzyl)-piperidin-4-ylamine piperidin-4-yl]-(6- (intermediate A2) and 6-methyl-5-nitro- chloro-2-methyl-3-nitro- pyridin-2-yl)- pyridine(commercially amine available) 33 405.89 N⁶-[1-(4-chloro-3- Method C1-(4-chloro-3-ethoxy- 406.4 ethoxy-benzyl)- benzyl)-piperidin-4-ylaminepiperidin-4-yl]-3- (intermediate A2) and 6- nitro-pyridine-2,6-chloro-3-nitro-pyridin-2- diamine ylamine (commercially available) 34424.37 [1-(4-chloro-3- Method E 1-(4-chloro-3-ethoxy- 424.1ethoxy-benzyl)- benzyl)-piperidin-4-ylamine piperidin-4-yl]-(6-(intermediate A2) and 2,6- chloro-4- dichloro-4-methoxymethyl-methoxymethyl- pyridine (intermediate D2) pyridin-2-yl)- amine 35 384.912-[1-(4-chloro-3- Method C 1-(4-chloro-3-ethoxy- 385.4 ethoxy-benzyl)-benzyl)-piperidin-4-ylamine piperidin-4- (intermediate A2) and 2-ylamino]-6-methyl- chloro-6-methyl- nicotinonitrile nicotinonitrile(commercially available) 36 413.92 [1-(4-chloro-3- Method E1-(4-chloro-3-ethoxy- 414.4 ethoxy-benzyl)- benzyl)-piperidin-4-ylaminepiperidin-4-yl]-(6- (intermediate A2) and 2- fluoro-quinolin-2-chloro-6-fluoro-quinoline yl)-amine (intermediate D1) 37 410.95[1-(4-chloro-3- Method C 1-(4-chloro-3-ethoxy- 411.5 ethoxy-benzyl)-benzyl)-piperidin-4-ylamine piperidin-4-yl]-(5- (intermediate A2) and 2-methyl- chloro-5-methyl- [1,6]naphthyridin- [1,6]naphthyridine2-yl)-amine (commercially available)

Example 386-[1-(3-Ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-nicotinonitrile

Step 1: 4-(5-Cyano-pyridin-2-ylamino)-piperidine-1-carboxylic acidtert-butyl ester

A mixture of 6-chloro-nicotinonitrile (2.1 g, 15.16 mmol, 1.0 equiv;commercially available) and 4-amino-piperidine-1-carboxylic acidtert-butyl ester (4.86 g, 24.25 mmol, 1.6 equiv; commercially available)in N-ethyl diisopropylamine (5 mL) and anhydrous DMF (10 mL) was stirredat 60° C. for 3 d. To the reaction mixture was added a sat. solution ofNa₂CO₃ (100 mL) and the crude extracted with ethyl acetate (3×100 mL).The combined organic phases were dried over MgSO₄, concentrated byevaporation under reduced pressure and the crude material purified withsilica column chromatography eluting with toluene/ethyl acetate (4:1) toprovide 2.90 g (63%) of the title compound. ¹H NMR (300 MHz, DMSO):δ1.24-1.42 (m, 2H), 1.41 (s, 9H), 1.84-1.89 (m, 2H), 2.85-2.94 (m, 2H),3.87-3.91 (m, 2H), 3.98 (br s, 1H), 6.54 (d, J=8.9 Hz, 1H), 7.53 (d,J=7.5 Hz, 1H), 7.66 (dd, J=8.9 Hz, J=2.1 Hz, 1H), 8.38 (d, J=2.1 Hz,1H). ¹³C NMR (75 MHz, DMSO): δ28.04, 31.19, 42.25, 47.12, 78.58, 94.49,108.62, 118.91, 138.53, 153.00, 153.89, 159.17. MS (ISP): 303.1 [M+H]⁺.

Step 2: 6-(Piperidin-4-ylamino)-nicotinonitrile dihydrochloride(Intermediate B2)

A solution of 4-(5-cyano-pyridin-2-ylamino)-piperidine-1-carboxylic acidtert-butyl ester (2.6 g, 8.60 mmol) in 4 M HCl in dioxane (20 mL) wasstirred at rt for 1 h. The solvent was removed under reduced pressureand the crude product used in the consecutive step without furtherpurification assuming quantitative deprotection and formation of thedihydrochloride salt. MS (ISP): 203.3 [M+H]⁺.

Step 3:6-[1-(3-Ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-nicotinonitrile

To a solution of 6-(piperidin-4-ylamino)-nicotinonitrile dihydrochloride(41.3 mg, 0.15 mmol, 1.0 equiv; intermediate B2) in ethanol (2 mL),acetic acid (72.1 mg, 1.2 mmol, 8.0 equiv) and N-ethyl diisopropylamine(77.6 mg, 0.6 mmol, 4.0 equiv) was added 3-ethoxy-4-methyl-benzaldehyde(29.6 mg, 0.18 mmol, 1.2 equiv; intermediate E10, vide infra) and themixture stirred at 55° C. After 1 h, sodium cyanoborohydride (47.1 mg,0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL), was added and themixture stirred at 55° C. over night. Removal of the solvent underreduced pressure and purification by preparative HPLC on reversed phaseeluting with a gradient of acetonitrile/water provided 20.5 mg (39%) ofthe title compound. MS (ISP): 350.7 [M+H]⁺.

The pyridine, quinoline, isoquinoline and pyrazine piperidineintermediates B3 to B14 were prepared following literature precedents oras described below.

Synthesis of Pyridine, Quinoline, Isoquinoline and Pyrazine PiperidineIntermediates B3 to B14 to be Used in Table 4

Intermediate B3 6-(Piperidin-4-ylamino)-nicotinamide dihydrochloride

Step 1: 4-(5-Carbamoyl-pyridin-2-ylamino)-piperidine-1-carboxylic acidtert-butyl ester

To a solution of 4-(5-cyano-pyridin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (0.40 g, 1.32 mmol, 1.0 equiv; example 38/step 1)in DMSO (2.5 mL) was added potassium carbonate (0.037 g, 0.27 mmol, 0.2equiv) and a solution of 30% hydrogen peroxide in water (0.27 mL, 0.30g, 2.65 mmol, 2.0 equiv). The reaction mixture was stirred for 1 h at rtand then extracted from water (50 mL) with ethyl acetate (3×50 mL). Thecombined organic phases were dried over MgSO₄ and concentrated byevaporation under reduced pressure yielding 0.63 g (74%) of the titlecompound, which was used in the consecutive step without furtherpurification. ¹H NMR (300 MHz, CDCl₃): δ1.38-1.46 (m, 2H), 1.46 (s, 9H),1.98-2.03 (m, 2H), 2.90-2.93 (m, 2H), 3.79-3.91 (m, 1H), 4.01-4.06 (m,2H), 5.48 (d, J=8.1 Hz, 1H), 6.39 (d, J=8.8 Hz, 1H), 6.59 (br s, 2H),7.87 (dd, J=8.8 Hz, J=2.1 Hz, 1H), 8.59 (d, J=2.1 Hz, 1H). ¹³C NMR (75MHz, CDCl₃): δ28.38, 31.75, 42.50, 48.18, 79.52, 106.81, 117.65, 136.65,148.75, 154.68, 159.45, 168.70. MS (ISP): 321.4 [M+H]⁺.

Step 2: 6-(Piperidin-4-ylamino)-nicotinamide dihydrochloride

A solution of 4-(5-carbamoyl-pyridin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (0.63 g, 1.97 mmol) in 4 M HCl in dioxane (20 mL)was stirred at rt for 1 h. The solvent was removed under reducedpressure and the crude product used in the consecutive step withoutfurther purification assuming quantitative deprotection and formation ofthe dihydrochloride salt. MS (ISP): 221.4 [M+H]⁺.

Intermediate B4 6-(Piperidin-4-ylamino)-nicotinic acid dihydrochloride

Step 1: 6-(1-tert-Butoxycarbonyl-piperidin-4-ylamino)-nicotinic acid

To a solution of 4-(5-cyano-pyridin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (1.00 g, 3.31 mmol, 1.0 equiv; example 38/step 1)in ethanol (10 mL) was added a solution of 5 M NaOH (3.31 mL, 16.54mmol, 5.0 equiv) and the reaction mixture heated by microwaveirradiation to 120° C. for 15 min. The solvent was evaporated underreduced pressure and the crude material purified by silica columnchromatography using a MPLC system (CombiFlash Companion, Isco Inc.)eluting with a gradient of dichloromethane/methanol providing 0.46 g(39%) of the title compound. ¹H NMR (300 MHz, DMSO): δ1.18-1.31 (m, 2H),1.40 (s, 9H), 1.84-1.88 (m, 2H), 2.83-2.93 (m, 2H), 3.86-3.90 (m, 2H),3.90-4.03 (m, 1H), 6.43 (d, J=8.8 Hz, 1H), 7.05 (d, J=8.1 Hz, 1H), 7.81(dd, J=8.8 Hz, J=2.2 Hz, 1H), 8.54 (d, J=2.2 Hz, 1H). MS (ISP): 322.4[M+H]⁺.

Step 2: 6-(Piperidin-4-ylamino)-nicotinic acid dihydrochloride

A solution of 6-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-nicotinicacid (0.46 g, 1.43 mmol) in ethanol (40 mL) and 4 M HCl in dioxane (40mL) was stirred at rt for 1 h. The solvent was removed under reducedpressure and the crude product used in the consecutive step withoutfurther purification assuming quantitative deprotection and formation ofthe dihydrochloride salt. MS (ISP): 222.3 [M+H]⁺.

Intermediate B5 Piperidin-4-yl-[5-(1H-tetrazol-5-yl)-pyridin-2-yl]-aminedihydrochloride

Step 1:4-[5-(1H-Tetrazol-5-yl)-pyridin-2-ylamino]-piperidine-1-carboxylic acidtert-butyl ester

To a solution of 4-(5-cyano-pyridin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (0.70 g, 2.32 mmol, 1.0 equiv; example 38/step 1)in anhydrous DMF (8 mL) was added sodium azide (0.45 g, 6.95 mmol, 3.0equiv) and ammonium chloride (0.37 g, 6.95 mmol, 3.0 equiv) and thereaction mixture heated by microwave irradiation to 150° C. for 1.5 h.The solvent was evaporated under reduced pressure and the crude materialpurified with column chromatography on silica eluting withdichloromethane/methanol (9:1) to yield 0.80 g (100%) of the titlecompound. ¹H NMR (300 MHz, CH₃OD): δ1.28-1.44 (m, 2H), 1.42 (s, 9H),1.89-1.93 (m, 2H), 2.85-2.93 (m, 2H), 3.81-3.90 (m, 1H), 3.93-3.97 (m,2H), 6.56 (d, J=8.9 Hz, 1H), 7.90 (dd, J=8.9 Hz, J=2.3 Hz, 1H), 8.52 (d,J=2.3 Hz, 1H). MS (ISP): 346.1 [M+H]⁺.

Step 2: Piperidin-4-yl-[5-(1H-tetrazol-5-yl)-pyridin-2-yl]-aminedihydrochloride

A solution of4-[5-(1H-tetrazol-5-yl)-pyridin-2-ylamino]-piperidine-1-carboxylic acidtert-butyl ester (0.80 g, 2.32 mmol) in 4 M HCl in dioxane (60 mL) wasstirred at rt for 2 h. The solvent was removed under reduced pressureand the crude product used in the consecutive step without furtherpurification assuming quantitative deprotection and formation of thedihydrochloride salt. MS (ISP): 246.4 [M+H]⁺.

Intermediate B6 Piperidin-4-yl-(5-trifluoromethyl-pyridin-2-yl)-aminedihydrochloride

Step 1: 4-(5-Trifluoromethyl-pyridin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester

A solution of 2-chloro-5-trifluoromethyl-pyridine (2.45 g, 13.50 mmol,1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylicacid tert-butyl ester (3.24 g, 16.19 mmol, 1.2 equiv; commerciallyavailable) in DMAc (12 mL) was heated by microwave irradiation to 155°C. for 6 h. A solution of 1 M NaOH (100 mL) was added and the reactionmixture extracted with ethyl acetate (3×100 mL). The combined organicphases were dried over MgSO₄, concentrated by evaporation under reducedpressure and the crude material purified with column chromatography onsilica eluting with a gradient of heptane/ethyl acetate (4:1→1:1) toyield 0.69 g (15%) of the title compound. ¹H NMR (300 MHz, CDCl₃):δ1.31-1.47 (m, 2H), 1.40 (s, 9H), 1.92-1.98 (m, 2H), 2.81-2.92 (m, 2H),3.72-3.83 (m, 1H), 3.97-4.03 (m, 2H), 4.77 (d, J=8.1 Hz, 1H), 6.31 (d,J=8.8 Hz, 1H), 7.62 (dd, J=8.8 Hz, J=2.2 Hz, 1H), 8.25 (br s, 1H). ¹³CNMR (75 MHz, CDCl₃): δ27.45, 31.17, 41.64, 47.51, 78.72, 105.86, 114.65(q, J=32.8 Hz), 123.58 (q, J=268.6 Hz), 133.26, 145.15, 153.76, 158.36.¹⁹F NMR (282 MHz, CDCl₃): 1-61.22. MS (ISP): 346.1 [M+H]⁺.

Step 2: Piperidin-4-yl-(5-trifluoromethyl-pyridin-2-yl)-aminedihydrochloride

A solution of4-(5-trifluoromethyl-pyridin-2-ylamino)-piperidine-1-carboxylic acidtert-butyl ester (0.69 g, 2.00 mmol) in ethanol (40 mL) and 4 M HCl indioxane (40 mL) was stirred at rt for 1 h. The solvent was removed underreduced pressure and the crude product used in the consecutive stepwithout further purification assuming quantitative deprotection andformation of the dihydrochloride salt. MS (ISP): 246.1 [M+H]⁺.

Intermediate B7 6-(Piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acidmethyl ester dihydrochloride

Step 1:6-(1-tert-Butoxycarbonyl-piperidin-4-ylamino)-4-trifluoromethyl-nicotinicacid methyl ester

A solution of 6-chloro-4-trifluoromethyl-nicotinic acid methyl ester(2.00 g, 8.35 mmol, 1.0 equiv; commercially available) and4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.01 g, 10.02mmol, 1.2 equiv; commercially available) in anhydrous DMF (10 mL) washeated by microwave irradiation to 110° C. for 4 h. A solution of 1 MNaOH (100 mL) was added and the reaction mixture extracted with ethylacetate (3×100 mL). The combined organic phases were dried over MgSO₄,concentrated by evaporation under reduced pressure and the crudematerial purified with column chromatography on silica eluting with agradient of heptane/ethyl acetate (5:1→3:1) to yield 1.65 g (49%) of thetitle compound. ¹H NMR (300 MHz, CDCl₃): δ1.36-1.41 (m, 2H), 1.40 (s,9H), 1.95-1.97 (m, 2H), 2.85-2.93 (m, 2H), 3.81 (s, 3H), 3.92-3.98 (m,1H), 3.98-4.05 (m, 2H), 5.12 (d, J=8.1 Hz, 1H), 6.59 (s, 1H), 8.68 (s,1H). ¹⁹F NMR (282 MHz, CDCl₃): δ−62.38. MS (ISP): 404.5 [M+H]⁺.

Step 2: 6-(Piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methylester dihydrochloride

A solution of6-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-4-trifluoromethyl-nicotinicacid methyl ester (1.65 g, 4.09 mmol) in THF (10 mL) and 4 M HCl indioxane (20 mL) was stirred at rt for 1 h. The solvent was removed underreduced pressure and the crude product used in the consecutive stepwithout further purification assuming quantitative deprotection andformation of the dihydrochloride salt. MS (ISP): 304.0 [M+H]⁺.

Intermediate B8 Piperidin-4-yl-quinolin-2-yl-amine dihydrochloride

Step 1: 4-(Quinolin-2-ylamino)-piperidine-1-carboxylic acid tert-butylester

To a degassed solution of 2-chloro-quinoline (1.00 g, 6.11 mmol, 1.0equiv; commercially available) and 4-amino-piperidine-1-carboxylic acidtert-butyl ester (1.47 g, 7.33 mmol, 1.2 equiv; commercially available)in dimethoxyethane (15 mL) was added KOtert-Bu (0.96 g, 8.56 mmol, 1.4equiv),(R)-(−)-1-[(S)-2-(dicyclohexyl-phosphino)-ferrocenyl]ethyl-di-tert-butylphosphine(3.39 mg, 0.0061 mmol, 0.1 mol %; Josiphos ligand [CAS RN 158923-11-6];commercially available from Strem Chemicals, USA) and palladium(II)acetate (1.37 mg, 0.0061 mmol, 0.1 mol %). The reaction mixture wasstirred at 90° C. for 4 h, concentrated by evaporation under reducedpressure and the residue purified by silica column chromatography usinga MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradientof heptane (+1% triethylamine)/ethyl acetate providing 1.0 g (50%) ofthe title compound. ¹H NMR (300 MHz, DMSO): δ1.28-1.41 (m, 2H), 1.42 (s,9H), 1.93-1.94 (m, 2H), 2.95-3.02 (m, 2H), 3.87-3.92 (m, 2H), 4.11-4.19(m, 1H), 6.74 (d, J=8.9 Hz, 1H), 6.94 (d, J=7.6 Hz, 1H), 7.10-7.16 (m,1H), 7.42-7.51 (m, 2H), 7.59 (d, J=7.6 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H).¹³C NMR (75 MHz, DMSO): δ28.07, 31.49, 42.41, 46.52, 78.52, 113.21,121.03, 122.80, 125.52, 127.42, 128.89, 136.18, 147.82, 153.92, 156.13.MS (ISP): 328.5 [M+H]⁺.

Step 2: Piperidin-4-yl-quinolin-2-yl-amine dihydrochloride

A solution of 4-(quinolin-2-ylamino)-piperidine-1-carboxylic acidtert-butyl ester (1.00 g, 3.05 mmol) in 4 M HCl in dioxane (100 mL) wasstirred at rt for 1 h. The solvent was removed under reduced pressureand the crude product used in the consecutive step without furtherpurification assuming quantitative deprotection and formation of thedihydrochloride salt. MS (ISP): 228.6 [M+H]⁺.

Intermediate B9 (4-Methyl-quinolin-2-yl)-piperidin-4-yl-aminedihydrochloride

Step 1: 4-(4-Methyl-quinolin-2-ylamino)-piperidine-1-carboxylic acidtert-butyl ester

To a degassed solution of 2-chloro-4-methyl-quinoline (1.00 g, 5.63mmol, 1.0 equiv; commercially available) and4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.35 g, 6.76mmol, 1.2 equiv; commercially available) in dimethoxyethane (15 mL) wasadded KOtert-Bu (0.88 g, 7.88 mmol, 1.4 equiv),(R)-(−)-1-[(S)-2-(dicyclohexyl-phosphino)-ferrocenyl]ethyl-di-tert-butylphosphine(3.12 mg, 0.0056 mmol, 0.1 mol %; Josiphos ligand [CAS RN 158923-11-6];commercially available from Strem Chemicals, USA) and palladium(II)acetate (1.26 mg, 0.0056 mmol, 0.1 mol %). The reaction mixture wasstirred at 90° C. for 18 h, concentrated by evaporation under reducedpressure and the residue purified by silica column chromatography usinga MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradientof heptane (+1% triethylamine)/ethyl acetate providing 0.54 g (28%) ofthe title compound. ¹H NMR (300 MHz, DMSO): δ1.31-1.40 (m, 2H), 1.41 (s,9H), 1.91-1.96 (m, 2H), 2.46 (s, 3H), 2.93-3.01 (m, 2H), 3.86-3.91 (m,2H), 4.11-4.17 (m, 1H), 6.59 (s, 1H), 6.80 (d, J=7.7 Hz, 1H), 7.13-7.17(m, 1H), 7.44-7.47 (m, 2H), 7.73 (d, J=7.7 Hz, 1H). ¹³C NMR (75 MHz,DMSO): δ18.16, 28.07, 31.57, 42.39, 46.37, 78.51, 112.89, 120.88,123.12, 123.64, 125.96, 128.69, 143.28, 147.91, 153.91, 155.93. MS(ISP): 342.5 [M+H]⁺.

Step 2: (4-Methyl-quinolin-2-yl)-piperidin-4-yl-amine dihydrochloride

A solution of 4-(4-methyl-quinolin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (0.54 g, 1.58 mmol) in 4 M HCl in dioxane (50 mL)was stirred at rt for 1 h. The solvent was removed under reducedpressure and the crude product used in the consecutive step withoutfurther purification assuming quantitative deprotection and formation ofthe dihydrochloride salt. MS (ISP): 242.4 [M+H]⁺.

Intermediate B10 (4-Chloro-quinolin-2-yl)-piperidin-4-yl-aminedihydrochloride

Step 1: 4-(4-Chloro-quinolin-2-ylamino)-piperidine-1-carboxylic acidtert-butyl ester

To a degassed solution of 2,4-dichloro-quinoline (1.00 g, 5.05 mmol, 1.0equiv; commercially available from Specs Research Laboratory, TheNetherlands) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester(1.21 g, 6.06 mmol, 1.2 equiv; commercially available) indimethoxyethane (15 mL) was added KOtert-Bu (0.79 g, 7.07 mmol, 1.4equiv),(R)-(−)-1-[(S)-2-(dicyclohexyl-phosphino)-ferrocenyl]ethyl-di-tert-butylphosphine(2.80 mg, 0.0051 mmol, 0.1 mol %; Josiphos ligand [CAS RN 158923-11-6];commercially available from Strem Chemicals, USA) and palladium(II)acetate (1.13 mg, 0.0051 mmol, 0.1 mol %). The reaction mixture wasstirred at 90° C. for 2 h, concentrated by evaporation under reducedpressure and the residue purified by silica column chromatography usinga MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradientof heptane (+1% triethylamine)/ethyl acetate providing 0.22 g (12%) ofthe title compound. ¹H NMR (300 MHz, DMSO): δ1.27-1.41 (m, 2H), 1.42 (s,9H), 1.93-1.97 (m, 2H), 2.95-3.03 (m, 2H), 3.86-3.90 (m, 2H), 4.09-4.16(m, 1H), 6.96 (s, 1H), 7.14 (d, J=7.7 Hz, 1H), 7.24-7.30 (m, 1H),7.55-7.57 (m, 2H), 7.86 (d, J=7.7 Hz, 1H). MS (ISP): 362.4 [M+H]⁻.

Step 2: (4-Chloro-quinolin-2-yl)-piperidin-4-yl-amine dihydrochloride

A solution of 4-(4-chloro-quinolin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (0.22 g, 0.61 mmol) in 4 M HCl in dioxane (30 mL)was stirred at rt for 1 h. The solvent was removed under reducedpressure and the crude product used in the consecutive step withoutfurther purification assuming quantitative deprotection and formation ofthe dihydrochloride salt. MS (ISP): 262.3 [M+H]⁺.

Intermediate B11 (8-Chloro-quinolin-2-yl)-piperidin-4-yl-aminedihydrochloride

Step 1: 4-(8-Chloro-quinolin-2-ylamino)-piperidine-1-carboxylic acidtert-butyl ester

To a degassed solution of 2,8-dichloro-quinoline (3.00 g, 15.15 mmol,1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylicacid tert-butyl ester (3.64 g, 18.18 mmol, 1.2 equiv; commerciallyavailable) in toluene (35 mL) was added KOtert-Bu (2.38 g, 21.21 mmol,1.4 equiv), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.38 g,0.61 mmol, 0.04 equiv) and tris(dibenzylideneacetone)-dipalladium(0)(0.31 g, 0.30 mmol, 0.02 equiv). The reaction mixture was stirred at 80°C. for 18 h, concentrated by evaporation under reduced pressure and theresidue purified by silica column chromatography using a MPLC system(CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane(+1% triethylamine)/ethyl acetate providing 1.73 g (31%) of the titlecompound. ¹H NMR (300 MHz, CDCl₃): δ1.37-1.51 (m, 2H), 1.48 (s, 9H),2.17-2.22 (m, 2H), 2.96-3.04 (m, 2H), 4.07-4.17 (m, 3H), 4.76 (d, J=7.0Hz, 1H), 6.64 (d, J=8.9 Hz, 1H), 7.11 (t, J=7.8 Hz, 1H), 7.49 (d, J=7.8Hz, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.80 (d, J=8.9 Hz, 1H). MS (ISP): 362.5[M+H]⁺.

Step 2: (8-Chloro-quinolin-2-yl)-piperidin-4-yl-amine dihydrochloride

A solution of 4-(8-chloro-quinolin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (1.30 g, 3.59 mmol) in 4 M HCl in dioxane (120 mL)was stirred at rt for 1 h. The solvent was removed under reducedpressure and the crude product used in the consecutive step withoutfurther purification assuming quantitative deprotection and formation ofthe dihydrochloride salt. MS (ISP): 262.3 [M+H]⁻.

Intermediate B12 Isoquinolin-1-yl-piperidin-4-yl-amine dihydrochloride

Step 1: 4-(Isoquinolin-1-ylamino)-piperidine-1-carboxylic acidtert-butyl ester

To a degassed solution of 1-chloro-isoquinoline (1.00 g, 6.11 mmol, 1.0equiv; commercially available) and 4-amino-piperidine-1-carboxylic acidtert-butyl ester (1.47 g, 7.34 mmol, 1.2 equiv; commercially available)in dimethoxyethane (15 mL) was added KOtert-Bu (0.96 g, 8.56 mmol, 1.4equiv),(R)-(−)-1-[(S)-2-(dicyclohexyl-phosphino)-ferrocenyl]ethyl-di-tert-butylphosphine(3.39 mg, 0.0061 mmol, 0.1 mol %; Josiphos ligand [CAS RN 158923-11-6];commercially available from Strem Chemicals, USA) and palladium(II)acetate (1.37 mg, 0.0061 mmol, 0.1 mol %). The reaction mixture wasstirred at 90° C. for 4 h, concentrated by evaporation under reducedpressure and the residue purified by silica column chromatography usinga MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradientof heptane (+1% triethylamine)/ethyl acetate providing 0.83 g (42%) ofthe title compound. ¹H NMR (300 MHz, DMSO): δ1.42-1.54 (m, 2H), 1.43 (s,9H), 1.92-1.93 (m, 2H), 2.89 (br s, 2H), 3.97-4.03 (m, 2H), 4.29-4.35(m, 1H), 6.88 (d, J=5.8 Hz, 1H), 7.04 (d, J=7.6 Hz, 1H), 7.47 (t, J=7.0Hz, 1H), 7.63 (t, J=7.0 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.86 (d, J=5.8Hz, 1H), 8.27 (d, J=8.6 Hz, 1H). ¹³C NMR (75 MHz, DMSO): δ28.09, 31.42,42.99, 47.39, 78.50, 109.41, 117.77, 123.10, 125.29, 126.38, 129.60,136.67, 141.31, 153.91, 154.49. MS (ISP): 328.5 [M+H]⁻.

Step 2: Isoquinolin-1-yl-piperidin-4-yl-amine dihydrochloride

A solution of 4-(isoquinolin-1-ylamino)-piperidine-1-carboxylic acidtert-butyl ester (0.83 g, 2.54 mmol) in 4 M HCl in dioxane (100 mL) wasstirred at rt for 1 h. The solvent was removed under reduced pressureand the crude product used in the consecutive step without furtherpurification assuming quantitative deprotection and formation of thedihydrochloride salt. MS (ISP): 228.6 [M+H]⁺.

Intermediate B13 (3-Chloro-isoquinolin-1-yl)-piperidin-4-yl-aminedihydrochloride

Step 1: 4-(3-Chloro-isoquinolin-1-ylamino)-piperidine-1-carboxylic acidtert-butyl ester

To a degassed solution of 1,3-dichloro-isoquinoline (3.00 g, 15.15 mmol,1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylicacid tert-butyl ester (3.64 g, 18.18 mmol, 1.2 equiv; commerciallyavailable) in toluene (35 mL) was added KOtert-Bu (2.38 g, 21.21 mmol,1.4 equiv), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.38 g,0.61 mmol, 0.04 equiv) and tris(dibenzylideneacetone)-dipalladium(0)(0.31 g, 0.30 mmol, 0.02 equiv). The reaction mixture was stirred at 80°C. for 18 h, concentrated by evaporation under reduced pressure and theresidue purified by silica column chromatography using a MPLC system(CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane(+1% triethylamine)/ethyl acetate providing 1.14 g (21%) of the titlecompound. ¹H NMR (300 MHz, DMSO): δ1.41-1.48 (m, 2H), 1.43 (s, 9H),1.90-1.91 (m, 2H), 2.87-2.93 (m, 2H), 3.97-4.02 (m, 2H), 4.24-4.27 (m,1H), 6.96 (s, 1H), 7.45-7.48 (m, 2H), 7.64-7.66 (m, 2H), 8.29 (d, J=8.4Hz, 1H). MS (ISN): 360.0 [M−H]⁻.

Step 2: (3-Chloro-isoquinolin-1-yl)-piperidin-4-yl-amine dihydrochloride

A solution of 4-(3-chloro-isoquinolin-1-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (1.14 g, 3.15 mmol) in 4 M HCl in dioxane (100 mL)was stirred at rt for 1 h. The solvent was removed under reducedpressure and the crude product used in the consecutive step withoutfurther purification assuming quantitative deprotection and formation ofthe dihydrochloride salt. MS (ISP): 262.3 [M+H]⁺.

Intermediate B14 5-(Piperidin-4-ylamino)-pyrazine-2-carboxylic acidmethyl ester dihydrochloride

Step 1: 4-(Isoquinolin-1-ylamino)-piperidine-1-carboxylic acidtert-butyl ester

A solution of 5-chloro-pyrazine-2-carboxylic acid methyl ester (1.33 g,7.68 mmol, 1.0 equiv; commercially available) and4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.00 g, 10.00mmol, 1.3 equiv; commercially available) in N-ethyl diisopropylamine (12mL) and acetonitrile (16 mL) was heated by microwave irradiation to 160°C. for 40 min. The solvent was evaporated under reduced pressure and theresidue purified by silica column chromatography using a MPLC system(CombiFlash Companion, Isco Inc.) eluting with a gradient ofheptane/ethyl acetate providing 1.62 g (63%) of the title compound. ¹HNMR (300 MHz, DMSO): δ1.27-1.41 (m, 2H), 1.41 (s, 9H), 1.86-1.90 (m,2H), 2.88-2.97 (m, 2H), 3.79 (s, 3H), 3.85-3.91 (m, 2H), 3.96-4.03 (m,1H), 7.93 (d, J=8.0 Hz, 1H), 7.95 (s, 1H), 8.58 (s, 1H). MS (ISP): 337.5[M+H]⁺.

Step 2: 5-(Piperidin-4-ylamino)-pyrazine-2-carboxylic acid methyl esterdihydrochloride

A solution of 4-(isoquinolin-1-ylamino)-piperidine-1-carboxylic acidtert-butyl ester (1.62 g, 4.82 mmol) in 4 M HCl in dioxane (100 mL) wasstirred at rt for 1 h. The solvent was removed under reduced pressureand the crude product used in the consecutive step without furtherpurification assuming quantitative deprotection and formation of thedihydrochloride salt. MS (ISP): 237.1 [M+H]⁺.

The aldehyde intermediates E1 to E21 were prepared following literatureprecedents or in analogy to literature precedents or as described below.

Synthesis of Aldehyde Intermediates E1 to E21 to be Used in Table 4

Intermediate E1 3-Ethoxy-4-fluoro-benzaldehyde

The title compound was prepared according to the procedure described forthe synthesis of 4-chloro-3-ethoxy-benzaldehyde (intermediate E2, videinfra) starting from 4-fluoro-3-hydroxy-benzoic acid in 73% overallyield after purification by flash column chromatography on silicaeluting with hexane/ethyl acetate (10:1). ¹H NMR (300 MHz, DMSO): δ1.32(t, J=7.0 Hz, 3H), 4.12 (q, J=7.0 Hz, 2H), 7.34-7.41 (m, 1H), 7.47-7.56(m, 2H), 9.87 (s, 1H). MS (ISP): 186.1 [M+NH₄]⁺.

Intermediate E2 4-Chloro-3-ethoxy-benzaldehyde [CAS RN 85259-46-7]

To a solution of 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17.4 mmol, 1.0equiv) in DMF (15 mL) was added K₂CO₃ (4.81 g, 34.8 mmol, 2.0 equiv) andethyl iodide (4.03 mL, 5.97 g, 38.2 mmol, 2.2 equiv). The reactionmixture was stirred for 6 h at rt, diluted with water (20 mL) andextracted with ethyl acetate (3×50 mL). The organic phases were driedover Na₂SO₄ and concentrated to afford 3.6 g (91%) of4-chloro-3-ethoxy-benzoic acid ethyl ester. The crude ester was thendissolved in THF (20 mL) and cooled to −78° C. under Ar. A solution ofdiisobutylaluminium hydride (95 mL, 95.0 mmol, 6.0 equiv; 1.0 M solutionin THF) was slowly added over a time period of 15 min, the cooling bathremoved on completion of addition and the reaction allowed to reach 0°C. After stirring for 1 h, the reaction was cooled to −78° C. and theexcess hydride quenched by cautious addition of a solution of 1 M HCl(10 mL). The mixture was brought to rt, the organic phase separated andthe aqueous layer extracted with ethyl acetate (3×100 mL). The combinedorganic phases were dried over Na₂SO₄ and concentrated by evaporationunder reduced pressure providing 2.94 g (100%) of4-chloro-3-ethoxy-benzyl alcohol. The crude alcohol (2.94 g, 15.75 mmol,1.0 equiv) was dissolved in dichloromethane (15 mL) and activated MnO₂(5.48 g, 63.0 mmol, 4.0 equiv) was added. The reaction mixture wasstirred for 16 h, after which time the reaction was filtered throughHyflo Super Cel and concentrated. The residue was purified by flashcolumn chromatography on silica eluting with heptane/ethyl acetate (4:1)to yield 1.51 g (52%) of the title compound. ¹H NMR (300 MHz, CDCl₃):δ1.51 (t, J=7.1 Hz, 3H), 4.19 (q, J=7.1 Hz, 2H), 7.37-7.42 (m, 2H), 7.55(d, J=9.0 Hz, 1H), 9.94 (s, 1H).

Intermediate E3 3,5-Diethoxy-benzaldehyde [CAS RN 120355-79-5]

The title compound was prepared analogously to3-ethoxy-4-methyl-benzaldehyde (intermediate E10, vide infra) byreaction of 3,5-dihydroxybenzaldehyde with ethyl iodide in DMF usingK₂CO₃ as base.

Intermediate E4 3,5-Diisopropoxy-benzaldehyde [CAS RN 94169-64-9]

To a solution of 3,5-dihydroxy-benzaldehyde (5.0 g, 36.20 mmol, 1.0equiv) in anhydrous DMF (30 mL) was added K₂CO₃ (15.0 g, 108.60 mmol,3.0 equiv) and 2-bromo-propane (13.36 g, 10.20 mL, 108.60 mmol, 3.0equiv) and the mixture stirred at 100° C. for 18 h. The K₂CO₃ wasremoved by filtration and the organic phase concentrated under reducedpressure. To the residue was added a sat. solution of NaCl (100 mL) andthe solution extracted with ethyl acetate (3×100 mL). The combinedorganic phases were dried over MgSO₄ and the product purified by silicacolumn chromatography using a MPLC system (CombiFlash Companion, IscoInc.) eluting with a gradient of heptane/ethyl acetate affording 6.64 g(83%) of the title compound and 0.59 g (9%) of3-hydroxy-5-isopropoxy-benzaldehyde (intermediate E19, vide infra). ¹HNMR (300 MHz, CDCl₃): δ1.35 (d, J=6.1 Hz, 12H), 4.59 (hept, J=6.1 Hz,2H), 6.66-6.68 (m, 1H), 6.96-6.97 (m, 2H), 9.88 (s, 1H). MS (ISP): 223.1[M+H]⁺.

Intermediate E5 3,5-Diethoxy-4-fluoro-benzaldehyde

Step 1: tert-Butyl-(4-fluoro-benzyloxy)-dimethyl-silane

To a solution of (4-fluoro-phenyl)-methanol (12.16 g, 96.4 mmol, 1.0equiv) in anhydrous DMF (50 mL) at 0° C. under Ar was added imidazole(7.22 g, 106.1 mmol, 1.1 equiv) and tert-butyl-chloro-dimethyl-silane(15.99 g, 106.1 mmol, 1.1 equiv). After the addition was completed thecooling bath was removed and the reaction stirred for 18 h at rt. Thereaction mixture was poured on ice, extracted with ethyl acetate (2×100mL) and the combined organic phases washed with a sat. solution ofNa₂CO₃ (2×100 mL) and NaCl (2×100 mL). The organic phase was dried overNa₂SO₄, concentrated by evaporation under reduced pressure yielding abrown oil that was purified by high vacuum distillation (bp 32-35° C. at0.1 mbar) to give 23.0 g (99%) of the title compound. ¹H NMR (400 MHz,CDCl₃): δ0.00 (s, 6H), 0.84 (s, 9H), 4.60 (s, 2H), 6.89-6.94 (m, 2H),7.16-7.20 (m, 2H). MS (EI): 183.1 [M-tert-Bu]⁺.

Step 2: 5-(tert-Butyl-dimethyl-silanyloxymethyl)-2-fluoro-phenol

To a solution of tert-butyl-(4-fluoro-benzyloxy)-dimethyl-silane (5.00g, 20.8 mmol, 1.0 equiv) in anhydrous THF (20 mL) was added at −78° C.under Ar a solution of sec-BuLi (17.6 mL, 22.8 mmol, 1.1 equiv; 1.3 Msolution in hexane) within 30 min. Then a solution of trimethyl borate(2.37 mL, 2.20 g, 20.8 mmol, 1.0 equiv) in anhydrous THF (7.5 mL) wasadded slowly within 30 min and the cooling bath removed. A solution ofconc. acetic acid (2.78 mL, 1.87 g, 31.2 mmol, 1.5 equiv) was slowlyadded followed by addition of a solution of 35% hydrogen peroxide inwater (2.0 mL, 2.23 g, 22.9 mmol, 1.1 equiv) and the reaction mixturekept at 0° C. for 30 min. After stirring at rt for an additional 4 h,the reaction was extracted with diethyl ether (2×100 mL) and thecombined organic phases washed with a solution of 10% NaOH (2×100 mL)and a sat. solution of NaCl (2×100 mL). The organic phase was dried overNa₂SO₄, concentrated by evaporation under reduced pressure and the crudematerial purified with column chromatography on silica eluting withhexane/ethyl acetate (19:1) providing 4.80 g (90%) of the titlecompound. ¹H NMR (400 MHz, CDCl₃): δ0.00 (s, 6H), 0.84 (s, 9H), 4.56 (s,2H), 4.97 (br s, 1H), 6.68-6.72 (m, 1H), 6.87-6.94 (m, 2H). MS (EI):256.2 [M]⁺.

Step 3:2-(tert-Butyl-dimethyl-silanyloxy)-4-(tert-butyl-dimethyl-silanyloxymethyl)-1-fluoro-benzene

To a solution of5-(tert-butyl-dimethyl-silanyloxymethyl)-2-fluoro-phenol (4.60 g, 17.9mmol, 1.0 equiv) in anhydrous DMF (20 mL) at 0° C. under Ar was addedimidazole (1.34 g, 19.7 mmol, 1.1 equiv) andtert-butyl-chloro-dimethyl-silane (2.97 g, 19.7 mmol, 1.1 equiv). Afterthe addition was completed the cooling bath was removed and the reactionstirred for 18 h at rt. The reaction mixture was poured on ice,extracted with ethyl acetate (2×100 mL) and the combined organic phaseswashed with a sat. solution of Na₂CO₃ (2×100 mL) and NaCl (2×100 mL).The organic phase was dried over Na₂SO₄ and concentrated by evaporationunder reduced pressure yielding 4.50 g (68%) of the title compound. ¹HNMR (400 MHz, CDCl₃): δ0.00 (s, 6H), 0.10 (s, 6H), 0.85 (s, 9H), 0.92(s, 9H), 4.55 (s, 2H), 6.71-6.74 (m, 1H), 6.80-6.83 (m, 1H), 6.87-6.92(m, 1H). MS (EI): 370.2 [M]⁺.

Step 4:3-(tert-Butyl-dimethyl-silanyloxy)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2-fluoro-phenol

To a solution of2-(tert-butyl-dimethyl-silanyloxy)-4-(tert-butyl-dimethyl-silanyloxymethyl)-1-fluoro-benzene(23.70 g, 63.9 mmol, 1.0 equiv) in anhydrous THF (130 mL) was added at−78° C. under Ar a solution of sec-BuLi (54.5 mL, 71.6 mmol, 1.1 equiv;1.3 M solution in hexane) within 30 min. Then a solution of trimethylborate (7.13 mL, 6.64 g, 63.9 mmol, 1.0 equiv) in anhydrous THF (30 mL)was added slowly within 30 min and the cooling bath removed. A solutionof conc. acetic acid (5.49 mL, 5.76 g, 95.9 mmol, 1.5 equiv) was slowlyadded followed by addition of a solution of 35% hydrogen peroxide inwater (6.2 mL, 6.83 g, 70.3 mmol, 1.1 equiv) and the reaction mixturekept at 0° C. for 30 min. After stirring at rt for an additional 4 h,the reaction was extracted with diethyl ether (2×100 mL) and thecombined organic phases washed with a solution of 10% NaOH (2×100 mL)and a sat. solution of NaCl (2×100 mL). The organic phase was dried overNa₂SO₄, concentrated by evaporation under reduced pressure and the crudematerial purified with column chromatography on silica eluting withhexane/ethyl acetate (19:1) providing 15.80 g (64%) of the titlecompound. ¹H NMR (400 MHz, CDCl₃): δ0.00 (s, 6H), 0.10 (s, 6H), 0.85 (s,9H), 0.91 (s, 9H), 4.50 (s, 2H), 4.93 (br s, 1H), 6.37 (d, J=5.6 Hz,1H), 6.47 (d, J=5.6 Hz, 1H). MS (EI): 329.2 [M-tert-Bu]⁺.

Step 5: tert-Butyl-(3,5-diethoxy-4-fluoro-benzyloxy)-dimethyl-silane

To a solution of3-(tert-butyl-dimethyl-silanyloxy)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2-fluoro-phenol(5.80 g, 15.0 mmol, 1.0 equiv) in DMF (60 mL) was added K₂CO₃ (4.56 g,33.0 mmol, 2.2 equiv) and ethyl bromide (2.46 mL, 3.60 g, 33.0 mmol, 2.2equiv) and the reaction mixture stirred under Ar at 60° C. for 5 h. TheK₂CO₃ was removed by filtration, the crude reaction mixture concentratedby evaporation under reduced pressure, the residue extracted with ethylacetate (3×100 mL), the combined organic phases washed with water (2×100ml) and dried over Na₂SO₄. The solvent was removed by evaporation underreduced pressure and the crude material purified with columnchromatography on silica eluting with hexane/ethyl acetate (99:1)providing 3.10 g (63%) of the title compound. ¹H NMR (400 MHz, CDCl₃):δ0.00 (s, 6H), 0.85 (s, 9H), 1.33 (t, J=7.0 Hz, 6H), 4.00 (q, J=7.0 Hz,4H), 4.55 (s, 2H), 6.47 (d, J=6.8 Hz, 2H). MS (ISP): 329.3 [M+H]⁺.

Step 6: (3,5-Diethoxy-4-fluoro-phenyl)-methanol

To a solution oftert-butyl-(3,5-diethoxy-4-fluoro-benzyloxy)-dimethyl-silane (1.20 g,3.65 mmol, 1.0 equiv) in methanol (8 mL) was added Dowex 50W-X8 (0.33 g,cation exchange resin) and the reaction mixture stirred under Ar at rtfor 22 h. The resin was removed by filtration and the reaction mixtureconcentrated by evaporation under reduced pressure yielding the titlecompound in quantitative yield (0.78 g). ¹H NMR (400 MHz, CDCl₃): S1.34(t, J=7.0 Hz, 6H), 1.57 (t, J=5.4 Hz, 1H), 4.01 (q, J=7.0 Hz, 4H), 4.51(d, J=5.4 Hz, 2H), 6.51 (d, J=6.8 Hz, 2H). MS (EI): 214.2 [M]⁺.

Step 7: 3,5-Diethoxy-4-fluoro-benzaldehyde

To a solution of (3,5-diethoxy-4-fluoro-phenyl)-methanol (2.30 g, 10.7mmol, 1.0 equiv) in 1,2-dichloroethane (50 mL) was added activated MnO₂(2.89 g, 33.3 mmol, 3.1 equiv). The reaction mixture was stirred for 21h at 50° C. and then filtered through Hyflo Super Cel providing afterevaporation of the solvent under reduced pressure 1.90 g (83%) of thetitle compound. ¹H NMR (400 MHz, CDCl₃): δ1.38 (t, J=7.0 Hz, 6H), 4.09(q, J=7.0 Hz, 4H), 7.04 (d, J=7.2 Hz, 2H), 9.75 (s, 1H). MS (EI): 212.1[M]⁺.

Intermediate E6 4-Chloro-3,5-diethoxy-benzaldehyde

Step 1: 4-Chloro-3,5-diethoxy-benzoic acid ethyl ester

To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (5.1 g,20.13 mmol, 1.0 equiv; prepared as described in I. Kompis and A. WickHelv. Chim. Acta 1977, 60, 3025-3034) in water (40 mL) and 37% HCl (40mL) at 0° C. was added sodium nitrite (1.67 g, 24.16 mmol, 1.2 equiv).After 10 min, copper(I) chloride (12.0 g, 120.81 mmol, 6.0 equiv) wasadded, the reaction mixture stirred for an additional 5 h at 0° C. andthen the ice bath removed. After stirring for 18 h, the crude reactionmixture was adjusted to pH=8 by addition of a solution of 1 M NaOH andthe aqueous layer extracted with ethyl acetate (3×100 mL). The combinedorganic phases were dried over MgSO₄, concentrated by evaporation underreduced pressure and the crude material purified by silica columnchromatography using a MPLC system (CombiFlash Companion, Isco Inc.)eluting with a gradient of heptane/ethyl acetate providing 5.0 g (91%)of the title compound. ¹H NMR (300 MHz, CDCl₃): δ1.32 (t, J=7.0 Hz, 4H),1.40 (t, J=7.0 Hz, 6H), 4.09 (q, J=7.0 Hz, 4H), 4.30 (q, J=7.0 Hz, 2H),7.18 (s, 2H). ¹³C NMR (75 MHz, CDCl₃): δ13.33, 13.66, 60.29, 64.16,105.75, 115.88, 128.25, 154.49, 165.01. MS (ISP): 273.3 [M+H]⁺.

Step 2: (4-Chloro-3,5-diethoxy-phenyl)-methanol

To a solution of 4-chloro-3,5-diethoxy-benzoic acid ethyl ester (5.0 g,18.33 mmol, 1.0 equiv) in dichloromethane (25 mL) was added slowly overa time period of 15 min under slight cooling to −30° C. a solution ofdiisobutylaluminium hydride (55.0 mL, 55.00 mmol, 3.0 equiv; 1.0 Msolution in THF). After 30 min, the excess hydride was quenched bycautious addition of methanol (10 mL) and water (2 mL). The mixture wasstirred for 30 min, a solution of 1 M HCl was added and the aqueouslayer extracted with ethyl acetate (3×100 mL). The combined organicphases were dried over MgSO₄ and concentrated by evaporation underreduced pressure providing 4.0 g (95%) of the title compound. ¹H NMR(300 MHz, CDCl₃): δ1.45 (t, J=7.0 Hz, 6H), 1.93 (br s, 1H), 4.09 (q,J=7.0 Hz, 4H), 4.62 (s, 2H), 6.57 (s, 2H). ¹³C NMR (75 MHz, CDCl₃):δ14.74, 64.96, 65.18, 104.30, 110.65, 140.29, 155.66. MS (ISP): 231.4[M+H]⁺.

Step 3: 4-Chloro-3,5-diethoxy-benzaldehyde

To a solution of (4-chloro-3,5-diethoxy-phenyl)-methanol (4.0 g, 17.34mmol, 1.0 equiv) in THF (40 mL) was added activated MnO₂ (15.08 g, 173.4mmol, 10.0 equiv) and the reaction mixture stirred for 18 h at rt.Filtration through Hyflo Super Cel and purification of the crudematerial by silica column chromatography using a MPLC system (CombiFlashCompanion, Isco Inc.) eluting with a gradient of heptanelethyl acetateprovided 3.7 g (92%) of the title compound. ¹H NMR (300 MHz, CDCl₃):δ1.50 (t, J=7.0 Hz, 6H), 4.19 (q, J=7.0 Hz, 4H), 7.07 (s, 2H), 9.89 (s,1H). ¹³C NMR (75 MHz, CDCl₃): δ14.61, 65.22, 106.26, 118.64, 135.08,156.22, 191.01. MS (EI): 229.4 [M]⁺.

Intermediate E7 4-Bromo-3,5-diethoxy-benzaldehyde [CAS RN 363166-11-4]

The title compound was prepared from 4-bromo-3,5-dihydroxy-benzoic acidas described in S. P. Dudek, H. D. Sikes and C. E. D. Chidsey J. Am.Chem. Soc. 2001, 123, 8033-8038.

Intermediate E8 4-Amino-3,5-diethoxy-benzaldehyde

Step 1: (4-Amino-3,5-diethoxy-phenyl)-methanol

To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (2.8 g,11.05 mmol, 1.0 equiv; prepared as described in I. Kompis, A. Wick Helv.Chim. Acta 1977, 60, 3025-3034) in dichloromethane (50 mL) at 0° C.under Ar was slowly added diisobutylaluminum hydride (27.6 mL, 27.64mmol, 2.5 equiv; 1.0 M solution in dichloromethane) over a time periodof 15 min and the cooling bath removed on completion of addition. Afterstirring for 18 h, the excess hydride was quenched by cautious additionof a sat. solution of potassium sodium tartrate (10 mL). The solidifiedmixture was extracted with dichloromethane (5×200 mL) and THF (2×150mL), the combined organic phases washed with water (3×100 mL), driedover MgSO₄, concentrated by evaporation under reduced pressure and thecrude material purified by column chromatography on silica eluting witha gradient of heptane/ethyl acetate (4:1→1:1) providing 1.10 g (47%) ofthe title compound. ¹H NMR (300 MHz, CDCl₃): 11.42 (t, J=7.0 Hz, 3H),3.82 (br s, 2H), 4.05 (q, J=7.0 Hz, 2H), 4.54 (s, 2H), 6.50 (s, 2H). ¹³CNMR (75 MHz, CDCl₃): δ15.03, 64.21, 66.00, 104.51, 125.44, 129.89,146.71. MS (ISP): 211.9 [M+H]⁺.

Step 2: 4-Amino-3,5-diethoxy-benzaldehyde

To a solution of (4-amino-3,5-diethoxy-phenyl)-methanol (0.79 g, 3.74mmol, 1.0 equiv) in DMF (20 mL) was added activated MnO₂ (1.63 g, 18.70mmol, 5.0 equiv). The reaction mixture was stirred for 24 h at rt,filtered through Hyflo Super Cel, the filtrate extracted with ethylacetate (3×50 mL) and the combined organic phases dried over MgSO₄providing 0.69 g (88%) of the title compound. ¹H NMR (300 MHz, DMSO):δ1.46 (t, J=7.0 Hz, 3H), 4.15 (q, J=7.0 Hz, 2H), 4.50 (br s, 2H), 7.04(s, 2H), 9.70 (s, 1H). MS (ISP): 210.0 [M+H]⁺.

Intermediate E9 3,5-Diethoxy-4-pyrrol-1-yl-benzaldehyde

Step 1: 3,5-Diethoxy-4-pyrrol-1-yl-benzoic acid ethyl ester

To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (3.0 g,11.84 mmol, 1.0 equiv; prepared as described in I. Kompis and A. WickHelv. Chim. Acta 1977, 60, 3025-3034) in heptane (10 mL) and conc.acetic acid (0.2 mL) was added 2,5-dimethoxy-tetrahydro-furan (1.88 g,14.21 mmol, 1.2 equiv). After heating to reflux for 5 h, a Dean-Starkapparatus was attached and the reaction mixture heated for an additionaltime period of 5 h. Filtration of the crude reaction mixture andcrystallization at 0° C. from heptane provided 2.94 g (82%) of the titlecompound. ¹H NMR (300 MHz, DMSO): δ1.15 (t, J=7.0 Hz, 6H), 1.27 (t,J=7.1 Hz, 3H), 3.98 (q, J=7.0 Hz, 4H), 4.28 (q, J=7.1 Hz, 2H), 6.07-6.08(m, 2H), 6.73-6.74 (m, 2H), 7.22 (s, 2H). ¹³C NMR (75 MHz, DMSO):δ14.11, 14.35, 61.06, 64.57, 106.87, 107.64, 122.61, 123.33, 129.29,153.75, 165.06. MS (ISP): 303.4 [M+H]⁺.

Step 2: 3,5-Diethoxy-4-pyrrol-1-yl-benzaldehyde

To a solution of 3,5-diethoxy-4-pyrrol-1-yl-benzoic acid ethyl ester(1.51 g, 4.98 mmol, 1.0 equiv) in toluene (5 mL) was added slowly over atime period of 15 min under slight cooling to 20° C. a solution ofdiisobutylaluminium hydride (8.9 mL, 12.45 mmol, 2.5 equiv; 20% solutionin toluene). After 1 h the excess hydride was quenched by cautiousaddition of water (10 mL) and a 28% solution of NaOH (2 mL). The mixturewas stirred for 30 min and the organic phase filtered over Hyflo SuperCel. The aqueous layer was extracted with toluene (2×50 mL), thecombined organic phases washed with a sat. solution of NaCl (2×50 mL)and concentrated by evaporation under reduced pressure to afford 1.30 g(100%) of (3,5-diethoxy-4-pyrrol-1-yl-phenyl)-methanol. The crudealcohol (1.30 g, 4.98 mmol, 1.0 equiv) was dissolved in toluene (20 mL)and activated MnO₂ (7.79 g, 89.5 mmol, 18.0 equiv) was added. Thereaction mixture was heated to reflux for 7 h, after which time thereaction mixture was filtered through Hyflo Super Cel and concentratedyielding 1.15 g (89% yield) of the title compound. ¹H NMR (300 MHz,DMSO): δ1.17 (t, J=7.0 Hz, 6H), 4.02 (q, J=7.0 Hz, 4H), 6.08-6.09 (m,2H), 6.75-6.76 (m, 2H), 7.25 (s, 2H), 9.89 (s, 1H). MS (ISP): 260.1[M+H]⁺.

Intermediate E10 3-Ethoxy-4-methyl-benzaldehyde [CAS RN 157143-20-9]

The title compound was prepared by reaction of commercially available3-hydroxy-4-methyl-benzaldehyde with ethyl iodide in DMF using K₂CO₃ asbase in analogy to the procedure described in M. J. Ashton, D. C. Cook,G. Fenton, J.-A. Karlsson, M. N. Palfreyman, D. Raeburn, A. J.Ratcliffe, J. E. Souness, S. Thurairatnam and N. Vicker J. Med. Chem.1994, 37, 1696-1703.

Intermediate E11 4-Methoxy-3-propoxy-benzaldehyde [CAS RN 5922-56-5]

The title compound was prepared by reaction of isovanillin with propyliodide in DMF using K₂CO₃ as base in analogy to the preparation of3-ethoxy-4-methyl-benzaldehyde (intermediate E10).

Intermediate E12 3-Isobutoxy-4-methoxy-benzaldehyde [CAS RN 57724-26-2]

The title compound was prepared by reaction of isovanillin with1-bromo-2-methyl propane as described in WO 04/000 806 A1 (Elbion AG).

Intermediate E13 3,5-Diethoxy-4-iodo-benzaldehyde [CAS RN 338454-05-0]

The title compound was prepared as described in WO 01/326 33 A1 (F.Hoffmann-La Roche AG).

Intermediate E14 3-Ethoxy-4-iodo-5-methoxymethoxy-benzaldehyde [CAS RN338451-02-8]

The title compound was prepared as described in WO 01/032 633 A1 (F.Hoffmann-La Roche AG).

Intermediate E15 3-Ethoxy-4-(1-ethyl-propoxy)-benzaldehyde

The title compound was prepared analogously to3-ethoxy-4-methyl-benzaldehyde (intermediate E10) by reaction of3-ethoxy-4-hydroxy-benzaldehyde with 3-bromo-pentane in DMF using K₂CO₃as base. MS (ISP): 237.1 [M+H]⁺.

Intermediate E16 3-Allyloxy-4-methoxy-benzaldehyde [CAS RN 225939-36-6]

The title compound was prepared analogously to3-ethoxy-4-methyl-benzaldehyde (intermediate E10) by reaction of3-hydroxy-4-methoxy-benzaldehyde with alkylbromide in DMF using K₂CO₃ asbase (see also A. W. White, R. Almassy, A. H. Calvert, N. J. Curtin, R.J. Griffin, Z. Hostomsky, K. Maegley, D. R. Newell, S. Srinivasan and B.T. Golding J. Med. Chem. 2000, 43, 4084-4097).

Intermediate E17 3-Butoxy-4-methoxy-benzaldehyde

The title compound was prepared analogously to3-ethoxy-4-methyl-benzaldehyde (intermediate E10) by reaction of3-hydroxy-4-methoxy-benzaldehyde with 4-bromo-butane in DMF using K₂CO₃as base. MS (ISP): 209.1 [M+H]⁺.

Intermediate E18 8-Ethoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde [CASRN 210404-30-9]

The title compound was prepared according to WO 011083 476 A1(Hoffmann-La Roche AG).

Intermediate E19 3-Hydroxy-5-isopropoxy-benzaldehyde

Isolated as a side-product in the synthesis of3,5-diisopropoxy-benzaldehyde (intermediate E4). ¹H NMR (300 MHz,CDCl₃): δ1.34 (d, J=6.1 Hz, 6H), 4.58 (hept, J=6.1 Hz, 1H), 6.28 (br s,1H), 6.68-6.69 (m, 1H), 6.95-6.98 (m, 2H), 9.85 (s, 1H). MS (ISN): 179.1[M−H]

Intermediate E20 2,6-Diethoxy-4-formyl-benzoic acid ethyl ester [CAS RN55687-55-3]

The title compound was prepared as described in DE 243 59 34 (F.Hoffmann-La Roche AG).

Intermediate E21 3-(2-Fluoro-ethoxy)-4-methoxy-benzaldehyde

To a solution of 3-hydroxy-4-methoxy-benzaldehyde (10.0 g, 66.0 mmol,1.0 equiv; commercially available) in anhydrous DMF (40 mL) was addedK₂CO₃ (13.6 g, 99.0 mmol, 1.5 equiv) and 1-bromo-2-fluoro-ethane (9.2mg, 72.0 mmol, 1.1 equiv) and the mixture stirred at rt for 48 h. TheK₂CO₃ was removed by filtration and the organic phase concentrated underreduced pressure. To the residue was added a sat. solution of NaCl (100mL) and the solution extracted with ethyl acetate (3×100 mL). Thecombined organic phases were dried over MgSO₄ and the productcrystallized from a mixture of isopropanol/diethylether to yield 12.69 g(97%) of the title compound. ¹H NMR (300 MHz, DMSO): δ3.89 (s, 3H),4.24-4.27 (m, 1H), 4.34-4.37 (m, 1H), 4.67-4.70 (m, 1H), 4.83-4.86 (m,1H), 7.20 (d, J=8.4 Hz, 1H), 7.43 (d, J=1.9 Hz, 1H), 7.59 (dd, J=8.4 Hz,J=1.9 Hz, 1H), 9.84 (s, 1H). MS (ISP): 198.6 [M+H]⁺.

Examples 39 to 188

According to the procedure described for the synthesis of example38/step 3 further pyridine, quinoline, isoquinoline and pyrazinederivatives have been synthesized from6-(piperidin-4-ylamino)-nicotinonitrile dihydrochloride (intermediateB2), 6-(piperidin-4-ylamino)-nicotinamide dihydrochloride (intermediateB3), 6-(piperidin-4-ylamino)-nicotinic acid dihydrochloride(intermediate B4),piperidin-4-yl-[5-(1H-tetrazol-5-yl)-pyridin-2-yl]-amine dihydrochloride(intermediate B5), piperidin-4-yl-(5-trifluoromethyl-pyridin-2-yl)-aminedihydrochloride (intermediate B6),6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl esterdihydrochloride (intermediate B7), piperidin-4-yl-quinolin-2-yl-aminedihydrochloride (intermediate B8),(4-methyl-quinolin-2-yl)-piperidin-4-yl-amine dihydrochloride(intermediate B9), (4-chloro-quinolin-2-yl)-piperidin-4-yl-aminedihydrochloride (intermediate B10),(8-chloro-quinolin-2-yl)-piperidin-4-yl-amine dihydrochloride(intermediate B11), isoquinolin-1-yl-piperidin-4-yl-aminedihydrochloride (intermediate B12),(3-chloro-isoquinolin-1-yl)-piperidin-4-yl-amine dihydrochloride(intermediate B13) and 5-(piperidin-4-ylamino)-pyrazine-2-carboxylicacid methyl ester dihydrochloride (intermediate B14) and the respectivebenzaldehyde intermediate as indicated in Table 4. The results arecompiled in Table 4 and comprise example 39 to example 188.

TABLE 4 ISP [M + H]⁺ or M − H]⁻ No MW Compound Name Starting Materialsfound 39 354.43 6-[1-(3-ethoxy-4- 6-(piperidin-4-ylamino)- [M + H]⁺fluoro-benzyl)- nicotinonitrile dihydrochloride 355.4piperidin-4-ylamino]- (intermediate B2) and 3-ethoxy- nicotinonitrile4-fluoro-benzaldehyde (intermediate E1) 40 370.88 6-[1-(4-chloro-3-6-(piperidin-4-ylamino)- [M + H]⁺ ethoxy-benzyl)- nicotinonitriledihydrochloride 371.2 piperidin-4-ylamino]- (intermediate B2) and4-chloro-3- nicotinonitrile ethoxy-benzaldehyde (intermediate E2) 41352.44 6-[1-(3-ethoxy-4- 6-(piperidin-4-ylamino)- [M + H]⁺hydroxy-benzyl)- nicotinonitrile dihydrochloride 352.6piperidin-4-ylamino]- (intermediate B2) and 3-ethoxy- nicotinonitrile4-hydroxy-benzaldehyde (commercially available) 42 380.496-[1-(3,5-diethoxy- 6-(piperidin-4-ylamino)- [M + H]⁺benzyl)-piperidin-4- nicotinonitrile dihydrochloride 380.7 ylamino]-(intermediate B2) and 3,5- nicotinonitrile diethoxy-benzaldehyde(intermediate E3) 43 408.55 6-[1-(3,5- 6-(piperidin-4-ylamino)- [M + H]⁺diisopropoxy-benzyl)- nicotinonitrile dihydrochloride 409.4piperidin-4-ylamino]- (intermediate B2) and 3,5- nicotinonitrilediisopropoxy-benzaldehyde (intermediate E4) 44 398.486-[1-(3,5-diethoxy-4- 6-(piperidin-4-ylamino)- [M + H]⁺ fluoro-benzyl)-nicotinonitrile dihydrochloride 399.1 piperidin-4-ylamino]-(intermediate B2) and 3,5- nicotinonitrilediethoxy-4-fluoro-benzaldehyde (intermediate E5) 45 414.946-[1-(4-chloro-3,5- 6-(piperidin-4-ylamino)- [M + H]⁺ diethoxy-benzyl)-nicotinonitrile dihydrochloride 414.7 piperidin-4-ylamino]-(intermediate B2) and 4-chloro- nicotinonitrile3,5-diethoxy-benzaldehyde (intermediate E6) 46 459.39 6-[1-(4-bromo-3,5-6-(piperidin-4-ylamino)- [M + H]⁺ diethoxy-benzyl)- nicotinonitriledihydrochloride 459.2 piperidin-4-ylamino]- (intermediate B2) and4-bromo- nicotinonitrile 3,5-diethoxy-benzaldehyde (intermediate E7) 47395.51 6-[1-(4-amino-3,5- 6-(piperidin-4-ylamino)- [M + H]⁺diethoxy-benzyl)- nicotinonitrile dihydrochloride 396.3piperidin-4-ylamino]- (intermediate B2) and 4-amino- nicotinonitrile3,5-diethoxy-benzaldehyde (intermediate E8) 48 445.576-[1-(3,5-diethoxy-4- 6-(piperidin-4-ylamino)- [M + H]⁺pyrrol-1-yl-benzyl)- nicotinonitrile dihydrochloride 445.8piperidin-4-ylamino]- (intermediate B2) and 3,5- nicotinonitrilediethoxy-4-pyrrol-1-yl- benzaldehyde (intermediate E9) 49 368.486-[1-(3-ethoxy-4- 6-(piperidin-4-ylamino)- [M + H]⁺ methyl-benzyl)-nicotinamide dihydrochloride 368.7 piperidin-4-ylamino]- (intermediateB3) and 3-ethoxy- nicotinamide 4-methyl-benzaldehyde (intermediate E10)50 372.44 6-[1-(3-ethoxy-4- 6-(piperidin-4-ylamino)- [M + H]⁺fluoro-benzyl)- nicotinamide dihydrochloride 372.6 piperidin-4-ylamino]-(intermediate B3) and 3-ethoxy- nicotinamide 4-fluoro-benzaldehyde(intermediate E1) 51 388.17 6-[1-(4-chloro-3- 6-(piperidin-4-ylamino)-[M + H]⁺ ethoxy-benzyl)- nicotinamide dihydrochloride 389.3piperidin-4-ylamino]- (intermediate B3) and 4-chloro-3- nicotinamideethoxy-benzaldehyde (intermediate E2) 52 370.45 6-[1-(3-ethoxy-4-6-(piperidin-4-ylamino)- [M + H]⁺ hydroxy-benzyl)- nicotinamidedihydrochloride 370.7 piperidin-4-ylamino]- (intermediate B3) and3-ethoxy- nicotinamide 4-hydroxy-benzaldehyde (commercially available)53 384.48 6-[1-(3-ethoxy)-4- 6-(piperidin-4-ylamino)- [M + H]⁺methoxy-benzyl)- nicotinamide dihydrochloride 384.6piperidin-4-ylamino]- (intermediate B3) and 3-ethoxy- nicotinamide4-methoxy-benzaldehyde (commercially available) 54 398.516-[1-(4-methoxy-3- 6-(piperidin-4-ylamino)- [M + H]⁺ propoxy-benzyl)-nicotinamide dihydrochloride 399.4 piperidin-4-ylamino]- (intermediateB3) and 4- nicotinamide methoxy-3-propoxy- benzaldehyde (intermediateE11) 55 412.53 6-[1-(3-isobutoxy-4- 6-(piperidin-4-ylamino)- [M + H]⁺methoxy-benzyl)- nicotinamide dihydrochloride 413.4piperidin-4-ylamino]- (intermediate B3) and 3- nicotinamideisobutoxy-4-methoxy- benzaldehyde (intermediate E12) 56 398.516-[1-(3,5-diethoxy- 6-(piperidin-4-ylamino)- [M + H]⁺benzyl)-piperidin-4- nicotinamide dihydrochloride 398.7 ylamino]-(intermediate B3) and 3,5- nicotinamide diethoxy-benzaldehyde(intermediate E3) 57 426.56 6-[1-(3,5- 6-(piperidin-4-ylamino)- [M + H]⁺diisopropoxy-benzyl)- nicotinamide dihydrochloride 426.8piperidin-4-ylamino]- (intermediate B3) and 3,5- nicotinamidediisopropoxy-benzaldehyde (intermediate E4) 58 416.226-[1-(3,5-diethoxy-4- 6-(piperidin-4-ylamino)- [M + H]⁺ fluoro-benzyl)-nicotinamide dihydrochloride 417.3 piperidin-4-ylamino]- (intermediateB3) and 3,5- nicotinamide diethoxy-4-fluoro-benzaldehyde (intermediateE5) 59 432.95 6-[1-(4-chloro-3,5- 6-(piperidin-4-ylamino)- [M + H]⁺diethoxy-benzyl)- nicotinamide dihydrochloride 432.7piperidin-4-ylamino]- (intermediate B3) and 4-chloro- nicotinamide3,5-diethoxy-benzaldehyde (intermediate E6) 60 413.52 6-[1-(4-amino-3,5-6-(piperidin-4-ylamino)- [M + H]⁺ diethoxy-benzyl)- nicotinamidedihydrochloride 413.7 piperidin-4-ylamino]- (intermediate B3) and4-amino- nicotinamide 3,5-diethoxy-benzaldehyde (intermediate E8) 61463.58 6-[1-(3,5-diethoxy-4- 6-(piperidin-4-ylamino)- [M + H]⁺pyrrol-1-yl-benzyl)- nicotinamide dihydrochloride 464.3piperidin-4-ylamino]- (intermediate B3) and 3,5- nicotinamidediethoxy-4-pyrrol-1-yl- benzaldehyde (intermediate E9) 62 369.466-[1-(3-ethoxy-4- 6-(piperidin-4-ylamino)- [M + H]⁺ methyl-benzyl)-nicotinamide dihydrochloride 369.7 piperidin-4-ylamino]- (intermediateB3) and 3-ethoxy- nicotinic acid 4-methyl-benzaldehyde (intermediateE10) 63 373.43 6-[1-(3-ethoxy-4- 6-(piperidin-4-ylamino)-nicotinic [M +H]⁺ fluoro-benzyl)- acid dihydrochloride 373.6 piperidin-4-ylamino]-(intermediate B4) and 3-ethoxy- nicotinic acid 4-fluoro-benzaldehyde(intermediate E1) 64 389.88 6-[1-(4-chloro-3-6-(piperidin-4-ylamino)-nicotinic [M + H]⁺ ethoxy-benzyl)- aciddihydrochloride 389.6 piperidin-4-ylamino]- (intermediate B4) and4-chloro-3- nicotinic acid ethoxy-benzaldehyde (intermediate E2) 65371.44 6-[1-(3-ethoxy-4- 6-(piperidin-4-ylamino)-nicotinic [M + H]⁺hydroxy-benzyl)- acid dihydrochloride 371.6 piperidin-4-ylamino]-(intermediate B4) and 3-ethoxy- nicotinic acid 4-hydroxy-benzaldehyde(commercially available) 66 385.46 6-[1-(3-ethoxy-4-6-(piperidin-4-ylamino)-nicotinic [M + H]⁺ methoxy-benzyl)- aciddihydrochloride 385.6 piperidin-4-ylamino]- (intermediate B4) and3-ethoxy- nicotinic acid 4-methoxy-benzaldehyde (commercially available)67 399.49 6-[1-(3,5-diethoxy- 6-(piperidin-4-ylamino)-nicotinic [M + H]⁺benzyl)-piperidin-4- acid dihydrochloride 399.7 ylamino]-nicotinic(intermediate B4) and 3,5- acid diethoxy-benzaldehyde (intermediate E3)68 427.54 6-[1-(3,5- 6-(piperidin-4-ylamino)-nicotinic [M + H]⁺diisopropoxy-benzyl)- acid dihydrochloride 427.7 piperidin-4-ylamino]-(intermediate B4) and 3,5- nicotinic acid diisopropoxy-benzaldehyde(intermediate E4) 69 417.48 6-[1-(3,5-diethoxy-4-6-(piperidin-4-ylamino)-nicotinic [M + H]⁺ fluoro-benzyl)- aciddihydrochloride 417.7 piperidin-4-ylamino]- (intermediate B4) and 3,5-nicotinic acid diethoxy-4-fluoro-benzaldehyde (intermediate E5) 70433.93 6-[1-(4-chloro-3,5- 6-(piperidin-4-ylamino)-nicotinic [M + H]⁺diethoxy-benzyl)- acid dihydrochloride 433.9 piperidin-4-ylamino]-(intermediate B4) and 4-chloro- nicotinic acid 3,5-diethoxy-benzaldehyde(intermediate E6) 71 413.17 [1-(4-chloro-3-piperidin-4-yl-[5-(1H-tetrazol-5- [M + H]⁺ ethoxy-benzyl)-yl)-pyridin-2-yl]-amine 414.3 piperidin-4-yl]-[5- dihydrochloride(intermediate (1H-tetrazol-5-yl)- B5) and 4-chloro-3-ethoxy-pyridin-2-yl]-amine benzaldehyde (intermediate E2) 72 409.22[1-(3-ethoxy-4- piperidin-4-yl-[5-(1H-tetrazol-5- [M + H]⁺methoxy-benzyl)- yl)-pyridin-2-yl]-amine 410.4 piperidin-4-yl]-[5-dihydrochloride (intermediate (1H-tetrazol-5-yl)- B5) and3-ethoxy-4-methoxy- pyridin-2-yl]-amine benzaldehyde (commerciallyavailable) 73 451.27 [1-(3,5-diisopropoxy-piperidin-4-yl-[5-(1H-tetrazol-5- [M + H]⁺ benzyl)-piperidin-4-yl)-pyridin-2-yl]-amine 452.3 yl]-[5-(1H-tetrazol-5- dihydrochloride(intermediate yl)-pyridin-2-yl]- B5) and 3,5-diisopropoxy- aminebenzaldehyde (intermediate E4) 74 441.23 [1-(3,5-diethoxy-4-piperidin-4-yl-[5-(1H-tetrazol-5- [M + H]⁺ fluoro-benzyl)-yl)-pyridin-2-yl]-amine 442.4 piperidin-4-yl]-[5- dihydrochloride(intermediate (1H-tetrazol-5-yl)- B5) and 3,5-diethoxy-4-fluoro-pyridin-2-yl]-amine benzaldehyde (intermediate E5) 75 501.15[1-(4-bromo-3,5- piperidin-4-yl-[5-(1H-tetrazol-5- [M + H]⁺diethoxy-benzyl)- yl)-pyridin-2-yl]-amine 502.5 piperidin-4-yl]-[5-dihydrochloride (intermediate (1H-tetrazol-5-yl)- B5) and4-bromo-3,5-diethoxy- pyridin-2-yl]-amine benzaldehyde (intermediate E7)76 393.45 [1-(3-ethoxy-4- piperidin-4-yl-(5-trifluoromethyl- [M + H]⁺methyl-benzyl)- pyridin-2-yl)-amine 394.3 piperidin-4-yl]-(5-dihydrochloride (intermediate trifluoromethyl- B6) and3-ethoxy-4-methyl- pyridin-2-yl)-amine benzaldehyde (intermediate E10)77 413.87 [1-(4-chloro-3- piperidin-4-yl-(5-trifluoromethyl- [M + H]⁺ethoxy-benzyl)- pyridin-2-yl)-amine 414.3 piperidin-4-yl]-(5-dihydrochloride (intermediate trifluoromethyl- B6) and4-chloro-3-ethoxy- pyridin-2-yl)-amine benzaldehyde (intermediate E2) 78409.45 [1-(3-ethoxy-4- piperidin-4-yl-(5-trifluoromethyl- [M + H]⁺methoxy-benzyl)- pyridin-2-yl)-amine 410.3 piperidin-4-yl]-(5-dihydrochloride (intermediate trifluoromethyl- B6) and3-ethoxy-4-methoxy- pyridin-2-yl)-amine benzaldehyde (commerciallyavailable) 79 423.48 [1-(4-methoxy-3- piperidin-4-yl-(5-trifluoromethyl-[M + H]⁺ propoxy-benzyl)- pyridin-2-yl)-amine 424.3 piperidin-4-yl]-(5-dihydrochloride (intermediate trifluoromethyl- B6) and4-methoxy-3-propoxy- pyridin-2-yl)-amine benzaldehyde (intermediate E11)80 423.48 [1-(3,5-diethoxy- piperidin-4-yl-(5-trifluoromethyl- [M + H]⁺benzyl)-piperidin-4- pyridin-2-yl)-amine 424.3 yl]-(5- dihydrochloride(intermediate trifluoromethyl- B6) and 3,5-diethoxy- pyridin-2-yl)-aminebenzaldehyde (intermediate E3) 81 441.47 [1-(3,5-diethoxy-4-piperidin-4-yl-(5-trifluoromethyl- [M + H]⁺ fluoro-benzyl)-pyridin-2-yl)-amine 442.4 piperidin-4-yl]-(5- dihydrochloride(intermediate trifluoromethyl- B6) and 3,5-diethoxy-4-fluoro-pyridin-2-yl)-amine benzaldehyde (intermediate E5) 82 549.37[1-(3,5-diethoxy-4- piperidin-4-yl-(5-trifluoromethyl- [M + H]⁺iodo-benzyl)- pyridin-2-yl)-amine 550.3 piperidin-4-yl]-(5-dihydrochloride (intermediate trifluoromethyl- B6) and3,5-diethoxy-4-iodo- pyridin-2-yl)-amine benzaldehyde (intermediate E13)83 565.37 [1-(3-ethoxy-4-iodo- piperidin-4-yl-(5-trifluoromethyl- [M +H]⁺ 5-methoxymethoxy- pyridin-2-yl)-amine 566.2 benzyl)-piperidin-4-dihydrochloride (intermediate yl]-(5- B6) and 3-ethoxy-4-iodo-5-trifluoromethyl- methoxymethoxy-benzaldehyde pyridin-2-yl)-amine(intermediate E14) 84 488.55 [1-(3,5-diethoxy-4-piperidin-4-yl-(5-trifluoromethyl- [M + H]⁺ pyrrol-1-yl-benzyl)-pyridin-2-yl)-amine 489.4 piperidin-4-yl]-(5- dihydrochloride(intermediate trifluoromethyl- B6) and 3,5-diethoxy-4-pyrrol-1-pyridin-2-yl)-amine yl-benzaldehyde (intermediate E9) 85 471.916-[1-(4-chloro-3- 6-(piperidin-4-ylamino)-4- [M + H]⁺ ethoxy-benzyl)-trifluoromethyl-nicotinic acid 472.2 piperidin-4-ylamino]- methyl esterdihydrochloride 4-trifluoromethyl- (intermediate B7) and 4-chloro-3-nicotinic acid methyl ethoxy-benzaldehyde ester (intermediate E2) 86453.46 6-[1-(3-ethoxy-4- 6-(piperidin-4-ylamino)-4- [M + H]⁺hydroxy-benzyl)- trifluoromethyl-nicotinic acid 454.2piperidin-4-ylamino]- methyl ester dihydrochloride 4-trifluoromethyl-(intermediate B7) and 3-ethoxy- nicotinic acid methyl4-hydroxy-benzaldehyde ester (commercially available) 87 467.496-[1-(3-ethoxy-4- 6-(piperidin-4-ylamino)-4- [M + H]⁺ methoxy-benzyl)-trifluoromethyl-nicotinic acid 468.3 piperidin-4-ylamino]- methyl esterdihydrochloride 4-trifluoromethyl- (intermediate B7) and 3-ethoxy-nicotinic acid methyl 4-methoxy-benzaldehyde ester (commerciallyavailable) 88 481.51 6-[1-(4-methoxy-3- 6-(piperidin-4-ylamino)-4- [M +H]⁺ propoxy-benzyl)- trifluoromethyl-nicotinic acid 482.3piperidin-4-ylamino]- methyl ester dihydrochloride 4-trifluoromethyl-(intermediate B7) and 4- nicotinic acid methyl methoxy-3-propoxy- esterbenzaldehyde (intermediate E11) 89 495.54 6-[1-(3-isobutoxy-4-6-(piperidin-4-ylamino)-4- [M + H]⁺ methoxy-benzyl)-trifluoromethyl-nicotinic acid 496.3 piperidin-4-ylamino]- methyl esterdihydrochloride 4-trifluoromethyl- (intermediate B7) and 3- nicotinicacid methyl isobutoxy-4-methoxy- ester benzaldehyde (intermediate E12)90 375.52 [1-(3-ethoxy-4- piperidin-4-yl-quinolin-2-yl- [M + H]⁺methyl-benzyl)- amine dihydrochloride 376.4 piperidin-4-yl]-(intermediate B8) and 3-ethoxy- quinolin-2-yl-amine4-methyl-benzaldehyde (intermediate E10) 91 379.48[1-(3-ethoxy-4-fluoro- piperidin-4-yl-quinolin-2-yl- [M + H]⁺benzyl)-piperidin-4- amine dihydrochloride 380.4 yl]-quinolin-2-yl-(intermediate B8) and 3-ethoxy- amine 4-fluoro-benzaldehyde(intermediate E1) 92 395.93 [1-(4-chloro-3-piperidin-4-yl-quinolin-2-yl- [M + H]⁺ ethoxy-benzyl)- aminedihydrochloride 396.3 piperidin-4-yl]- (intermediate B8) and 4-chloro-3-quinolin-2-yl-amine ethoxy-benzaldehyde (intermediate E2) 93 391.51[1-(3-ethoxy-4- piperidin-4-yl-quinolin-2-yl- [M + H]⁺ methoxy-benzyl)-amine dihydrochloride 392.2 piperidin-4-yl]- (intermediate B8) and3-ethoxy- quinolin-2-yl-amine 4-methoxy-benzaldehyde (commerciallyavailable) 94 447.62 {1-[3-ethoxy-4-(1- piperidin-4-yl-quinolin-2-yl-[M + H]⁺ ethyl-propoxy)- amine dihydrochloride 448.2benzyl]-piperidin-4- (intermediate B8) and 3-ethoxy- yl}-quinolin-2-yl-4-(1-ethyl-propoxy)- amine benzaldehyde (intermediate E15) 95 405.54[1-(4-methoxy-3- piperidin-4-yl-quinolin-2-yl- [M + H]⁺ propoxy-benzyl)-amine dihydrochloride 406.4 piperidin-4-yl]- (intermediate B8) and 4-quinolin-2-yl-amine methoxy-3-propoxy- benzaldehyde (intermediate E11)96 403.53 [1-(3-allyloxy-4- piperidin-4-yl-quinolin-2-yl- [M + H]⁺methoxy-benzyl)- amine dihydrochloride 404.5 piperidin-4-yl]-(intermediate B8) and 3-allyloxy- quinolin-2-yl-amine4-methoxy-benzaldehyde (intermediate E16) 97 419.57 [1-(3-butoxy-4-piperidin-4-yl-quinolin-2-yl- [M + H]⁺ methoxy-benzyl)- aminedihydrochloride 420.3 piperidin-4-yl]- (intermediate B8) and 3-butoxy-quinolin-2-yl-amine 4-methoxy-benzaldehyde (intermediate E17) 98 419.57[1-(3-isobutoxy-4- piperidin-4-yl-quinolin-2-yl- [M + H]⁺methoxy-benzyl)- amine dihydrochloride 420.4 piperidin-4-yl]-(intermediate B8) and 3- quinolin-2-yl-amine isobutoxy-4-methoxy-benzaldehyde (intermediate E12) 99 443.59 [1-(8-ethoxy-2,2-piperidin-4-yl-quinolin-2-yl- [M + H]⁺ dimethyl-2H- aminedihydrochloride 444.4 chromen-6-ylmethyl)- (intermediate B8) and8-ethoxy- piperidin-4-yl]- 2,2-dimethyl-2H-chromene-6-quinolin-2-yl-amine carbaldehyde (intermediate E18) 100 405.54[1-(3,5-diethoxy- piperidin-4-yl-quinolin-2-yl- [M + H]⁺benzyl)-piperidin-4- amine dihydrochloride 406.4 yl]-quinolin-2-yl-(intermediate B8) and 3,5- amine diethoxy-benzaldehyde (intermediate E3)101 391.51 3-isopropoxy-5-[4- piperidin-4-yl-quinolin-2-yl- [M + H]⁺(quinolin-2-ylamino)- amine dihydrochloride 392.2 piperidin-1-ylmethyl]-(intermediate B8) and 3-hydroxy- phenol 5-isopropoxy-benzaldehyde(intermediate E19) 102 433.60 [1-(3,5-diisopropoxy-piperidin-4-yl-quinolin-2-yl- [M + H]⁺ benzyl)-piperidin-4- aminedihydrochloride 434.4 yl]-quinolin-2-yl- (intermediate B8) and 3,5-amine diisopropoxy-benzaldehyde (intermediate E4) 103 423.53[1-(3,5-diethoxy-4- piperidin-4-yl-quinolin-2-yl- [M + H]⁺fluoro-benzyl)- amine dihydrochloride 424.3 piperidin-4-yl]-(intermediate B8) and 3,5- quinolin-2-yl-aminediethoxy-4-fluoro-benzaldehyde (intermediate E5) 104 439.99[1-(4-chloro-3,5- piperidin-4-yl-quinolin-2-yl- [M + H]⁺diethoxy-benzyl)- amine dihydrochloride 440.4 piperidin-4-yl]-(intermediate B8) and 4-chloro- quinolin-2-yl-amine3,5-diethoxy-benzaldehyde (intermediate E6) 105 484.44 [1-(4-bromo-3,5-piperidin-4-yl-quinolin-2-yl- [M + H]⁺ diethoxy-benzyl)- aminedihydrochloride 484.3 piperidin-4-yl]- (intermediate B8) and 4-bromo-quinolin-2-yl-amine 3,5-diethoxy-benzaldehyde (intermediate E7) 106420.56 [1-(4-amino-3,5- piperidin-4-yl-quinolin-2-yl- [M + H]⁺diethoxy-benzyl)- amine dihydrochloride 421.3 piperidin-4-yl]-(intermediate B8) and 4-amino- quinolin-2-yl-amine3,5-diethoxy-benzaldehyde (intermediate E8) 107 470.62[1-(3,5-diethoxy-4- piperidin-4-yl-quinolin-2-yl- [M + H]⁺pyrrol-1-yl-benzyl)- amine dihydrochloride 471.4 piperidin-4-yl]-(intermediate B8) and 3,5- quinolin-2-yl-amine diethoxy-4-pyrrol-1-yl-benzaldehyde (intermediate E9) 108 389.54 [1-(3-ethoxy-4-(4-methyl-quinolin-2-yl)- [M + H]⁺ methyl-benzyl)- piperidin-4-yl-amine390.4 piperidin-4-yl]-(4- dihydrochloride (intermediatemethyl-quinolin-2- B9) and 3-ethoxy-4-methyl- yl)-amine benzaldehyde(intermediate E10) 109 393.51 [1-(3-ethoxy-4-fluoro-(4-methyl-quinolin-2-yl)- [M + H]⁺ benzyl)-piperidin-4-piperidin-4-yl-amine 394.4 yl]-(4-methyl- dihydrochloride (intermediatequinolin-2-yl)-amine B9) and 3-ethoxy-4-fluoro- benzaldehyde(intermediate E1) 110 409.96 [1-(4-chloro-3- (4-methyl-quinolin-2-yl)-[M + H]⁺ ethoxy-benzyl)- piperidin-4-yl-amine 410.4 piperidin-4-yl]-(4-dihydrochloride (intermediate methyl-quinolin-2- B9) and4-chloro-3-ethoxy- yl)-amine benzaldehyde (intermediate E2) 111 405.54[1-(3-ethoxy-4- (4-methyl-quinolin-2-yl)- [M + H]⁺ methoxy-benzyl)-piperidin-4-yl-amine 406.5 piperidin-4-yl]-(4- dihydrochloride(intermediate methyl-quinolin-2- B9) and 3-ethoxy-4-methoxy- yl)-aminebenzaldehyde (commercially available) 112 405.54 3-isopropoxy-5-[4-(4-(4-methyl-quinolin-2-yl)- [M + H]⁺ methyl-quinolin-2-piperidin-4-yl-amine 406.5 ylamino)-piperidin-1- dihydrochloride(intermediate ylmethyl]-phenol B9) and 3-hydroxy-5-isopropoxy-benzaldehyde (intermediate E19) 113 447.62 [1-(3,5-diisopropoxy-(4-methyl-quinolin-2-yl)- [M + H]⁺ benzyl)-piperidin-4-piperidin-4-yl-amine 448.2 yl]-(4-methyl- dihydrochloride (intermediatequinolin-2-yl)-amine B9) and 3,5-diisopropoxy- benzaldehyde(intermediate E4) 114 437.56 [1-(3,5-diethoxy-4-(4-methyl-quinolin-2-yl)- [M + H]⁺ fluoro-benzyl)- piperidin-4-yl-amine438.4 piperidin-4-yl]-(4- dihydrochloride (intermediatemethyl-quinolin-2- B9) and 3,5-diethoxy-4-fluoro- yl)-amine benzaldehyde(intermediate E5) 115 454.01 [1-(4-chloro-3,5- (4-methyl-quinolin-2-yl)-[M + H]⁺ diethoxy-benzyl)- piperidin-4-yl-amine 454.3piperidin-4-yl]-(4- dihydrochloride (intermediate methyl-quinolin-2- B9)and 4-chloro-3,5-diethoxy- yl)-amine benzaldehyde (intermediate E6) 116498.47 [1-(4-bromo-3,5- (4-methyl-quinolin-2-yl)- [M + H]⁺diethoxy-benzyl)- piperidin-4-yl-amine 498.3 piperidin-4-yl]-(4-dihydrochloride (intermediate methyl-quinolin-2- B9) and4-bromo-3,5-diethoxy- yl)-amine benzaldehyde (intermediate E7) 117434.58 [1-(4-amino-3,5- (4-methyl-quinolin-2-yl)- [M + H]⁺diethoxy-benzyl)- piperidin-4-yl-amine 435.5 piperidin-4-yl]-(4-dihydrochloride (intermediate methyl-quinolin-2- B9) and4-amino-3,5-diethoxy- yl)-amine benzaldehyde (intermediate E8) 118484.64 [1-(3,5-diethoxy-4- (4-methyl-quinolin-2-yl)- [M + H]⁺pyrrol-1-yl-benzyl)- piperidin-4-yl-amine 485.5 piperidin-4-yl]-(4-dihydrochloride (intermediate methyl-quinolin-2- B9) and3,5-diethoxy-4-pyrrol-1- yl)-amine yl-benzaldehyde (intermediate E9) 119409.96 (4-chloro-quinolin-2- (4-chloro-quinolin-2-yl)- [M + H]⁺yl)-[1-(3-ethoxy-4- piperidin-4-yl-amine 410.4 methyl-benzyl)-dihydrochloride (intermediate piperidin-4-yl]-amine B10) and3-ethoxy-4-methyl- benzaldehyde (intermediate E10) 120 430.38[1-(4-chloro-3- (4-chloro-quinolin-2-yl)- [M + H]⁺ ethoxy-benzyl)-piperidin-4-yl-amine 430.4 piperidin-4-yl]-(4- dihydrochloride(intermediate chloro-quinolin-2-yl)- B10) and 4-chloro-3-ethoxy- aminebenzaldehyde (intermediate E2) 121 474.43 [1-(4-chloro-3,5-(4-chloro-quinolin-2-yl)- [M + H]⁺ diethoxy-benzyl)-piperidin-4-yl-amine 474.2 piperidin-4-yl]-(4- dihydrochloride(intermediate chloro-quinolin-2-yl)- B10) and 4-chloro-3,5-diethoxy-amine benzaldehyde (intermediate E6) 122 455.00 [1-(4-amino-3,5-(4-chloro-quinolin-2-yl)- [M + H]⁺ diethoxy-benzyl)-piperidin-4-yl-amine 455.3 piperidin-4-yl]-(4- dihydrochloride(intermediate chloro-quinolin-2-yl)- B10) and 4-amino-3,5-diethoxy-amine benzaldehyde (intermediate E8) 123 409.96 (8-chloro-quinolin-2-(8-chloro-quinolin-2-yl)- [M + H]⁺ yl)-[1-(3-ethoxy-4-piperidin-4-yl-amine 410.3 methyl-benzyl)- dihydrochloride (intermediatepiperidin-4-yl]-amine B11) and 3-ethoxy-4-methyl- benzaldehyde(intermediate E10) 124 430.38 [1-(4-chloro-3- (8-chloro-quinolin-2-yl)-[M + H]⁺ ethoxy-benzyl)- piperidin-4-yl-amine 430.3 piperidin-4-yl]-(8-dihydrochloride (intermediate chloro-quinolin-2-yl)- B11) and4-chloro-3-ethoxy- amine benzaldehyde (intermediate E2) 125 411.934-[4-(8-chloro- (8-chloro-quinolin-2-yl)- [M + H]⁺ quinolin-2-ylamino)-piperidin-4-yl-amine 412.2 piperidin-1-ylmethyl]- dihydrochloride(intermediate 2-ethoxy-phenol B11) and 3-ethoxy-4-hydroxy- benzaldehyde(commercially available) 126 425.96 (8-chloro-quinolin-2-(8-chloro-quinolin-2-yl)- [M + H]⁺ yl)-[1-(3-ethoxy-4-piperidin-4-yl-amine 426.2 methoxy-benzyl)- dihydrochloride(intermediate piperidin-4-yl]-amine B11) and 3-ethoxy-4-methoxy-benzaldehyde (commercially available) 127 482.07 (8-chloro-quinolin-2-(8-chloro-quinolin-2-yl)- [M + H]⁺ yl)-{1-[3-ethoxy-4-(1-piperidin-4-yl-amine 482.4 ethyl-propoxy)- dihydrochloride (intermediatebenzyl]-piperidin-4- B11) and 3-ethoxy-4-(1-ethyl- yl}-aminepropoxy)-benzaldehyde (intermediate E15) 128 439.99(8-chloro-quinolin-2- (8-chloro-quinolin-2-yl)- [M + H]⁺yl)-[1-(4-methoxy-3- piperidin-4-yl-amine 440.3 propoxy-benzyl)-dihydrochloride (intermediate piperidin-4-yl]-amine B11) and4-methoxy-3-propoxy- benzaldehyde (intermediate E11) 129 437.97[1-(3-allyloxy-4- (8-chloro-quinolin-2-yl)- [M + H]⁺ methoxy-benzyl)-piperidin-4-yl-amine 438.2 piperidin-4-yl]-(8- dihydrochloride(intermediate chloro-quinolin-2-yl)- B11) and 3-allyloxy-4-methoxy-amine benzaldehyde (intermediate E16) 130 454.01 [1-(3-butoxy-4-(8-chloro-quinolin-2-yl)- [M + H]⁺ methoxy-benzyl)- piperidin-4-yl-amine454.4 piperidin-4-yl]-(8- dihydrochloride (intermediatechloro-quinolin-2-yl)- B11) and 3-butoxy-4-methoxy- amine benzaldehyde(intermediate E17) 131 454.01 (8-chloro-quinolin-2-(8-chloro-quinolin-2-yl)- [M + H]⁺ yl)-[1-(3-isobutoxy-4-piperidin-4-yl-amine 454.4 methoxy-benzyl)- dihydrochloride(intermediate piperidin-4-yl]-amine B11) and 3-isobutoxy-4-methoxy-benzaldehyde (intermediate E12) 132 478.04 (8-chloro-quinolin-2-(8-chloro-quinolin-2-yl)- [M + H]⁺ yl)-[1-(8-ethoxy-2,2-piperidin-4-yl-amine 478.2 dimethyl-2H- dihydrochloride (intermediatechromen-6-ylmethyl)- B11) and 8-ethoxy-2,2-dimethyl-piperidin-4-yl]-amine 2H-chromene-6-carbaldehyde (intermediate E18) 133439.99 (8-chloro-quinolin-2- (8-chloro-quinolin-2-yl)- [M + H]⁺yl)-[1-(3,5-diethoxy- piperidin-4-yl-amine 440.3 benzyl)-piperidin-4-dihydrochloride (intermediate yl]-amine B11) and 3,5-diethoxy-benzaldehyde (intermediate E3) 134 512.05 4-[4-(8-chloro-(8-chloro-quinolin-2-yl)- [M + H]⁺ quinolin-2-ylamino)-piperidin-4-yl-amine 512.3 piperidin-1-ylmethyl]- dihydrochloride(intermediate 2,6-diethoxy-benzoic B11) and 2,6-diethoxy-4-formyl- acidethyl ester benzoic acid ethyl ester (intermediate E20) 135 457.98(8-chloro-quinolin-2- (8-chloro-quinolin-2-yl)- [M + H]⁺yl)-[1-(3,5-diethoxy- piperidin-4-yl-amine 458.2 4-fluoro-benzyl)-dihydrochloride (intermediate piperidin-4-yl]-amine B11) and3,5-diethoxy-4-fluoro- benzaldehyde (intermediate E5) 136 518.89[1-(4-bromo-3,5- (8-chloro-quinolin-2-yl)- [M + H]⁺ diethoxy-benzyl)-piperidin-4-yl-amine 520.2 piperidin-4-yl]-(8- dihydrochloride(intermediate chloro-quinolin-2-yl)- B11) and 4-bromo-3,5-diethoxy-amine benzaldehyde (intermediate E7) 137 505.06 (8-chloro-quinolin-2-(8-chloro-quinolin-2-yl)- [M + H]⁺ yl)-[1-(3,5-diethoxy-piperidin-4-yl-amine 505.2 4-pyrrol-1-yl-benzyl)- dihydrochloride(intermediate piperidin-4-yl]-amine B11) and 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (intermediate E9) 138 375.52 [1-(3-ethoxy-4-isoquinolin-1-yl-piperidin-4-yl- [M + H]⁺ methyl-benzyl)- aminedihydrochloride 376.4 piperidin-4-yl]- (intermediate B12) and 3-ethoxy-isoquinolin-1-yl- 4-methyl-benzaldehyde amine (intermediate E10) 139379.48 [1-(3-ethoxy-4-fluoro- isoquinolin-1-yl-piperidin-4-yl- [M + H]⁺benzyl)-piperidin-4- amine dihydrochloride 380.4 yl]-isoquinolin-1-yl-(intermediate B12) and 3-ethoxy- amine 4-fluoro-benzaldehyde(intermediate E1) 140 395.93 [1-(4-chloro-3-isoquinolin-1-yl-piperidin-4-yl- [M + H]⁺ ethoxy-benzyl)- aminedihydrochloride 396.3 piperidin-4-yl]- (intermediate B12) and 4-chloro-isoquinolin-1-yl- 3-ethoxy-benzaldehyde amine (intermediate E2) 141391.51 [1-(3-ethoxy-4- isoquinolin-1-yl-piperidin-4-yl- [M + H]⁺methoxy-benzyl)- amine dihydrochloride 392.2 piperidin-4-yl]-(intermediate B12) and 3-ethoxy- isoquinolin-1-yl-4-methoxy-benzaldehyde amine (commercially available) 142 405.54isoquinolin-1-yl-[1- isoquinolin-1-yl-piperidin-4-yl- [M + H]⁺(4-methoxy-3- amine dihydrochloride 406.4 propoxy-benzyl)- (intermediateB12) and 4- piperidin-4-yl]-amine methoxy-3-propoxy- benzaldehyde(intermediate E11) 143 403.53 [1-(3-allyloxy-4-isoquinolin-1-yl-piperidin-4-yl- [M + H]⁺ methoxy-benzyl)- aminedihydrochloride 404.5 piperidin-4-yl]- (intermediate B12) and 3-isoquinolin-1-yl- allyloxy-4-methoxy-benzaldehyde amine (intermediateE16) 144 419.57 [1-(3-butoxy-4- isoquinolin-1-yl-piperidin-4-yl- [M +H]⁺ methoxy-benzyl)- amine dihydrochloride 420.4 piperidin-4-yl]-(intermediate B12) and 3-butoxy- isoquinolin-1-yl-4-methoxy-benzaldehyde amine (intermediate E17) 145 419.57[1-(3-isobutoxy-4- isoquinolin-1-yl-piperidin-4-yl- [M + H]⁺methoxy-benzyl)- amine dihydrochloride 420.4 piperidin-4-yl]-(intermediate B12) and 3- isoquinolin-1-yl- isobutoxy-4-methoxy- aminebenzaldehyde (intermediate E12) 146 443.59 [1-(8-ethoxy-2,2-isoquinolin-1-yl-piperidin-4-yl- [M + H]⁺ dimethyl-2H- aminedihydrochloride 444.4 chromen-6-ylmethyl)- (intermediate B12) and8-ethoxy- piperidin-4-yl]- 2,2-dimethyl-2H-chromene-6- isoquinolin-1-yl-carbaldehyde (intermediate E18) amine 147 405.54 [1-(3,5-diethoxy-isoquinolin-1-yl-piperidin-4-yl- [M + H]⁺ benzyl)-piperidin-4- aminedihydrochloride 406.4 yl]-isoquinolin-1-yl- (intermediate B12) and 3,5-amine diethoxy-benzaldehyde (intermediate E3) 148 391.513-isopropoxy-5-[4- isoquinolin-1-yl-piperidin-4-yl- [M + H]⁺(isoquinolin-1- amine dihydrochloride 392.2 ylamino)-piperidin-1-(intermediate B12) and 3- ylmethyl]-phenol hydroxy-5-isopropoxy-benzaldehyde (intermediate E19) 149 433.60 [1-(3,5-diisopropoxy-isoquinolin-1-yl-piperidin-4-yl- [M + H]⁺ benzyl)-piperidin-4- aminedihydrochloride 434.4 yl]-isoquinolin-1-yl- (intermediate B12) and 3,5-amine diisopropoxy-benzaldehyde (intermediate E4) 150 423.53[1-(3,5-diethoxy-4- isoquinolin-1-yl-piperidin-4-yl- [M + H]⁺fluoro-benzyl)- amine dihydrochloride 424.3 piperidin-4-yl]-(intermediate B12) and 3,5- isoquinolin-1-yl-diethoxy-4-fluoro-benzaldehyde amine (intermediate E5) 151 439.99[1-(4-chloro-3,5- isoquinolin-1-yl-piperidin-4-yl- [M + H]⁺diethoxy-benzyl)- amine dihydrochloride 440.4 piperidin-4-yl]-(intermediate B12) and 4-chloro- isoquinolin-1-yl-3,5-diethoxy-benzaldehyde amine (intermediate E6) 152 484.44[1-(4-bromo-3,5- isoquinolin-1-yl-piperidin-4-yl- [M + H]⁺diethoxy-benzyl)- amine dihydrochloride 484.3 piperidin-4-yl]-(intermediate B12) and 4-bromo- isoquinolin-1-yl-3,5-diethoxy-benzaldehyde amine (intermediate E7) 153 470.62[1-(3,5-diethoxy-4- isoquinolin-1-yl-piperidin-4-yl- [M + H]⁺pyrrol-1-yl-benzyl)- amine dihydrochloride 471.4 piperidin-4-yl]-(intermediate B12) and 3,5- isoquinolin-1-yl- diethoxy-4-pyrrol-1-yl-amine benzaldehyde (intermediate E9) 154 409.96 (3-chloro-isoquinolin-(3-chloro-isoquinolin-1-yl)- [M + H]⁺ 1-yl)-[1-(3-ethoxy-4-piperidin-4-yl-amine 410.4 methyl-benzyl)- dihydrochloride (intermediatepiperidin-4-yl]-amine B13) and 3-ethoxy-4-methyl- benzaldehyde(intermediate E10) 155 413.92 (3-chloro-isoquinolin-(3-chloro-isoquinolin-1-yl)- [M + H]⁺ 1-yl)-[1-(3-ethoxy-4-piperidin-4-yl-amine 414.3 fluoro-benzyl)- dihydrochloride (intermediatepiperidin-4-yl]-amine B13) and 3-ethoxy-4-fluoro- benzaldehyde(intermediate E1) 156 430.38 [1-(4-chloro-3-(3-chloro-isoquinolin-1-yl)- [M + H]⁺ ethoxy-benzyl)-piperidin-4-yl-amine 430.4 piperidin-4-yl]-(3- dihydrochloride(intermediate chloro-isoquinolin-1- B13) and 4-chloro-3-ethoxy-yl)-amine benzaldehyde (intermediate E2) 157 411.93 4-[4-(3-chloro-(3-chloro-isoquinolin-1-yl)- [M + H]⁺ isoquinolin-1-piperidin-4-yl-amine 412.5 ylamino)-piperidin-1- dihydrochloride(intermediate ylmethyl]-2-ethoxy- B13) and 3-ethoxy-4-hydroxy- phenolbenzaldehyde (commercially available) 158 425.96 (3-chloro-isoquinolin-(3-chloro-isoquinolin-1-yl)- [M + H]⁺ 1-yl)-[1-(3-ethoxy-4-piperidin-4-yl-amine 426.3 methoxy-benzyl)- dihydrochloride(intermediate piperidin-4-yl]-amine B13) and 3-ethoxy-4-methoxy-benzaldehyde (commercially available) 159 461.94 (3-chloro-isoquinolin-(3-chloro-isoquinolin-1-yl)- [M + H]⁺ 1-yl)-[1-(4- piperidin-4-yl-amine462.4 difluoromethoxy-3- dihydrochloride (intermediate ethoxy-benzyl)-B13) and 4-difluoromethoxy-3- piperidin-4-yl]-amine ethoxy-benzaldehyde(commercially available) 160 454.01 (3-chloro-isoquinolin-(3-chloro-isoquinolin-1-yl)- [M + H]⁺ 1-yl)-[1-(3-ethoxy-4-piperidin-4-yl-amine 454.3 isopropoxy-benzyl)- dihydrochloride(intermediate piperidin-4-yl]-amine B13) and 3-ethoxy-4-isopropoxy-benzaldehyde (commercially available) 161 468.04 (3-chloro-isoquinolin-(3-chloro-isoquinolin-1-yl)- [M + H]⁺ 1-yl)-[1-(3-ethoxy-4-piperidin-4-yl-amine 468.4 isobutoxy-benzyl)- dihydrochloride(intermediate piperidin-4-yl]-amine B13) and 3-ethoxy-4-isobutoxy-benzaldehyde (commercially available) 162 439.99 (3-chloro-isoquinolin-(3-chloro-isoquinolin-1-yl)- [M + H]⁺ 1-yl)-[1-(4-methoxy-piperidin-4-yl-amine 440.4 3-propoxy-benzyl)- dihydrochloride(intermediate piperidin-4-yl]-amine B13) and 4-methoxy-3-propoxy-benzaldehyde (intermediate E11) 163 437.97 [1-(3-allyloxy-4-(3-chloro-isoquinolin-1-yl)- [M + H]⁺ methoxy-benzyl)-piperidin-4-yl-amine 438.3 piperidin-4-yl]-(3- dihydrochloride(intermediate chloro-isoquinolin-1- B13) and 3-allyloxy-4-methoxy-yl)-amine benzaldehyde (intermediate E16) 164 454.01 [1-(3-butoxy-4-(3-chloro-isoquinolin-1-yl)- [M + H]⁺ methoxy-benzyl)-piperidin-4-yl-amine 454.2 piperidin-4-yl]-(3- dihydrochloride(intermediate chloro-isoquinolin-1- B13) and 3-butoxy-4-methoxy-yl)-amine benzaldehyde (intermediate E17) 165 454.01(3-chloro-isoquinolin- (3-chloro-isoquinolin-1-yl)- [M + H]⁺1-yl)-[1-(3-isobutoxy- piperidin-4-yl-amine 454.3 4-methoxy-benzyl)-dihydrochloride (intermediate piperidin-4-yl]-amine B13) and3-isobutoxy-4-methoxy- benzaldehyde (intermediate E12) 166 478.04(3-chloro-isoquinolin- (3-chloro-isoquinolin-1-yl)- [M + H]⁺1-yl)-[1-(8-ethoxy- piperidin-4-yl-amine 478.2 2,2-dimethyl-2H-dihydrochloride (intermediate chromen-6-ylmethyl)- B13) and8-ethoxy-2,2-dimethyl- piperidin-4-yl]-amine 2H-chromene-6-carbaldehyde(intermediate E18) 167 439.99 (3-chloro-isoquinolin-(3-chloro-isoquinolin-1-yl)- [M + H]⁺ 1-yl)-[1-(3,5-piperidin-4-yl-amine 440.4 diethoxy-benzyl)- dihydrochloride(intermediate piperidin-4-yl]-amine B13) and 3,5-diethoxy- benzaldehyde(intermediate E3) 168 457.98 (3-chloro-isoquinolin-(3-chloro-isoquinolin-1-yl)- [M + H]⁺ 1-yl)-[1-(3,5-piperidin-4-yl-amine 458.4 diethoxy-4-fluoro- dihydrochloride(intermediate benzyl)-piperidin-4- B13) and 3,5-diethoxy-4-fluoro-yl]-amine benzaldehyde (intermediate E5) 169 474.43 [1-(4-chloro-3,5-(3-chloro-isoquinolin-1-yl)- [M + H]⁺ diethoxy-benzyl)-piperidin-4-yl-amine 474.2 piperidin-4-yl]-(3- dihydrochloride(intermediate chloro-isoquinolin-1- B13) and 4-chloro-3,5-diethoxy-yl)-amine benzaldehyde (intermediate E6) 170 518.89 [1-(4-bromo-3,5-(3-chloro-isoquinolin-1-yl)- [M + H]⁺ diethoxy-benzyl)-piperidin-4-yl-amine 520.2 piperidin-4-yl]-(3- dihydrochloride(intermediate chloro-isoquinolin-1- B13) and 4-bromo-3,5-diethoxy-yl)-amine benzaldehyde (intermediate E7) 171 455.00 [1-(4-amino-3,5-(3-chloro-isoquinolin-1-yl)- [M + H]⁺ diethoxy-benzyl)-piperidin-4-yl-amine 455.4 piperidin-4-yl]-(3- dihydrochloride(intermediate chloro-isoquinolin-1- B13) and 4-amino-3,5-diethoxy-yl)-amine benzaldehyde (intermediate E8) 172 384.48 5-[1-(3-ethoxy-4-5-(piperidin-4-ylamino)- [M + H]⁺ methyl-benzyl)- pyrazine-2-carboxylicacid methyl 384.4 piperidin-4-ylamino]- ester dihydrochloridepyrazine-2-carboxylic (intermediate B14) and 3-ethoxy- acid methyl ester4-methyl-benzaldehyde (intermediate E10) 173 388.44 5-[1-(3-ethoxy-4-5-(piperidin-4-ylamino)- [M + H]⁺ fluoro-benzyl)- pyrazine-2-carboxylicacid methyl 389.3 piperidin-4-ylamino]- ester dihydrochloridepyrazine-2-carboxylic (intermediate B14) and 3-ethoxy- acid methyl ester4-fluoro-benzaldehyde (intermediate E1) 174 404.90 5-[1-(4-chloro-3-5-(piperidin-4-ylamino)- [M + H]⁺ ethoxy-benzyl)- pyrazine-2-carboxylicacid methyl 405.8 piperidin-4-ylamino]- ester dihydrochloridepyrazine-2-carboxylic (intermediate B14) and 4-chloro- acid methyl ester4-ethoxy-benzaldehyde (intermediate E2) 175 386.45 5-[1-(3-ethoxy-4-5-(piperidin-4-ylamino)- [M + H]⁺ hydroxy-benzyl)- pyrazine-2-carboxylicacid methyl 387.3 piperidin-4-ylamino]- ester dihydrochloridepyrazine-2-carboxylic (intermediate B14) and 3-ethoxy- acid methyl ester4-hydroxy-benzaldehyde (commercially available) 176 400.485-[1-(3-ethoxy-4- 5-(piperidin-4-ylamino)- [M + H]⁺ methoxy-benzyl)-pyrazine-2-carboxylic acid methyl 401.3 piperidin-4-ylamino]- esterdihydrochloride pyrazine-2-carboxylic (intermediate B14) and 3-ethoxy-acid methyl ester 4-methoxy-benzaldehyde (commercially available) 177428.53 5-[1-(3-ethoxy-4- 5-(piperidin-4-ylamino)- [M + H]⁺isopropoxy-benzyl)- pyrazine-2-carboxylic acid methyl 429.4piperidin-4-ylamino]- ester dihydrochloride pyrazine-2-carboxylic(intermediate B14) and 3-ethoxy- acid methyl ester4-isopropoxy-benzaldehyde (commercially available) 178 414.515-[1-(4-methoxy-3- 5-(piperidin-4-ylamino)- [M + H]⁺ propoxy-benzyl)-pyrazine-2-carboxylic acid methyl 415.4 piperidin-4-ylamino]- esterdihydrochloride pyrazine-2-carboxylic (intermediate B14) and 4- acidmethyl ester methoxy-3-propoxy- benzaldehyde (intermediate E11) 179418.47 5-{1-[3-(2-fluoro- 5-(piperidin-4-ylamino)- [M + H]⁺ethoxy)-4-methoxy- pyrazine-2-carboxylic acid methyl 419.2benzyl]-piperidin-4- ester dihydrochloride ylamino}-pyrazine-2-(intermediate B14) and 3-(2- carboxylic acid methylfluoro-ethoxy)-4-methoxy- ester benzaldehyde (Intermediate E21) 180428.53 5-[1-(3-isobutoxy-4- 5-(piperidin-4-ylamino)- [M + H]⁺methoxy-benzyl)- pyrazine-2-carboxylic acid methyl 429.4piperidin-4-ylamino]- ester dihydrochloride pyrazine-2-carboxylic(intermediate B14) and 3- acid methyl ester isobutoxy-4-methoxy-benzaldehyde (intermediate E12) 181 452.55 5-[1-(8-ethoxy-2,2-5-(piperidin-4-ylamino)- [M + H]⁺ dimethyl-2H- pyrazine-2-carboxylicacid methyl 453.2 chromen-6-ylmethyl)- ester dihydrochloridepiperidin-4-ylamino]- (intermediate B14) and 8-ethoxy-pyrazine-2-carboxylic 2,2-dimethyl-2H-chromene-6- acid methyl estercarbaldehyde (intermediate E18) 182 414.51 5-[1-(3,5-diethoxy-5-(piperidin-4-ylamino)- [M + H]⁺ benzyl)-piperidin-4-pyrazine-2-carboxylic acid methyl 415.4 ylamino]-pyrazine-2- esterdihydrochloride carboxylic acid methyl (intermediate B14) and 3,5- esterdiethoxy-benzaldehyde (intermediate E3) 183 442.56 5-[1-(3,5-5-(piperidin-4-ylamino)- [M + H]⁺ diisopropoxy-benzyl)-pyrazine-2-carboxylic acid methyl 443.4 piperidin-4-ylamino]- esterdihydrochloride pyrazine-2-carboxylic (intermediate B14) and 3,5- acidmethyl ester diisopropoxy-benzaldehyde (intermediate E4) 184 432.505-[1-(3,5-diethoxy-4- 5-(piperidin-4-ylamino)- [M + H]⁺ fluoro-benzyl)-pyrazine-2-carboxylic acid methyl 433.3 piperidin-4-ylamino]- esterdihydrochloride pyrazine-2-carboxylic (intermediate B14) and 3,5- acidmethyl ester diethoxy-4-fluoro-benzaldehyde (intermediate E5) 185 448.955-[1-(4-chloro-3,5- 5-(piperidin-4-ylamino)- [M + H]⁺ diethoxy-benzyl)-pyrazine-2-carboxylic acid methyl 449.2 piperidin-4-ylamino]- esterdihydrochloride pyrazine-2-carboxylic (intermediate B14) and 4-chloro-acid methyl ester 3,5-diethoxy-benzaldehyde (intermediate E6) 186 493.415-[1-(4-bromo-3,5- 5-(piperidin-4-ylamino)- [M + H]⁺ diethoxy-benzyl)-pyrazine-2-carboxylic acid methyl 495.3 piperidin-4-ylamino]- esterdihydrochloride pyrazine-2-carboxylic (intermediate B14) and 4-bromo-acid methyl ester 3,5-diethoxy-benzaldehyde (intermediate E7) 187 429.525-[1-(4-amino-3,5- 5-(piperidin-4-ylamino)- [M + H]⁺ diethoxy-benzyl)-pyrazine-2-carboxylic acid methyl 430.4 piperidin-4-ylamino]- esterdihydrochloride pyrazine-2-carboxylic (intermediate B14) and 4-amino-acid methyl ester 3,5-diethoxy-benzaldehyde (intermediate E8) 188 479.585-[1-(3,5-diethoxy-4- 5-(piperidin-4-ylamino)- [M + H]⁺pyrrol-1-yl-benzyl)- pyrazine-2-carboxylic acid methyl 480.3piperidin-4-ylamino]- ester dihydrochloride pyrazine-2-carboxylic(intermediate B14) and 3,5- acid methyl ester diethoxy-4-pyrrol-1-yl-benzaldehyde (intermediate E9)

Example 1892-[1-(3-Ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-isonicotinonitrile

Step 1: 4-(4-Cyano-pyridin-2-ylamino)-piperidine-1-carboxylic acidtert-butyl ester

A solution of 2-chloro-isonicotinonitrile (2.00 g, 14.43 mmol, 1.0equiv; commercially available) and 4-amino-piperidine-1-carboxylic acidtert-butyl ester (3.18 g, 15.88 mmol, 1.1 equiv; commercially available)in DMAc (10 mL) was heated by microwave irradiation to 150° C. for 30min. The solvent was evaporated under reduced pressure and the crudematerial purified with column chromatography on silica eluting withheptane/ethyl acetate (1:1) to yield 0.30 g (7%) of the title compound.¹H NMR (300 MHz, CDCl₃): δ1.25-1.42 (m, 2H), 1.43 (s, 9H), 1.93-1.97 (m,2H), 2.83-2.93 (m, 2H), 3.71-3.81 (m, 1H), 3.97-4.02 (m, 2H), 4.77 (d,J=8.1 Hz, 1H), 6.51 (s, 1H), 6.66 (d, J=5.2 Hz, 1H), 8.11 (d, J=5.2 Hz,1H). MS (ISP): 303.0 [M+H]⁺.

Step 2: 2-(Piperidin-4-ylamino)-isonicotinonitrile dihydrochloride(Intermediate B15)

A solution of 4-(4-cyano-pyridin-2-ylamino)-piperidine-1-carboxylic acidtert-butyl ester (0.30 g, 1.00 mmol) in 4 M HCl in dioxane (15 mL) wasstirred at rt for 1 h. The solvent was removed under reduced pressureand the crude product used in the consecutive step without furtherpurification assuming quantitative deprotection and formation of thedihydrochloride salt. MS (ISP): 203.1 [M+H]⁺.

Step 3:2-[1-(3-Ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-isonicotinonitrile

To a solution of 2-(piperidin-4-ylamino)-isonicotinonitriledihydrochloride (43.0 mg, 0.18 mmol, 1.0 equiv; intermediate B15) inethanol (2 mL), acetic acid (54.1 mg, 0.9 mmol, 5.0 equiv) andtriethylamine (36.4 mg, 0.36 mmol, 2.0 equiv) was added3-ethoxy-4-methyl-benzaldehyde (36.1 mg, 0.22 mmol, 1.2 equiv;intermediate E10) and the mixture stirred at 50° C. After 1 h, sodiumcyanoborohydride (13.8 mg, 0.22 mmol, 1.2 equiv), dissolved in ethanol(0.5 mL), was added and the mixture stirred at 50° C. over night.Removal of the solvent under reduced pressure and purification bypreparative HPLC on reversed phase eluting with a gradient ofacetonitrile/water provided 1.8 mg (3%) of the title compound. MS (ISP):351.5 [M+H]⁺.

Example 1902-[1-(3-Ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-isonicotinamide

The title compound was isolated as a side-product in the synthesis of2-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-isonicotinonitrile(example 189) after purification by preparative HPLC on reversed phaseeluting with a gradient of acetonitrile/water in a yield of 10.5 mg(16%). MS (ISP): 369.3 [M+H]⁻.

Example 1912-[1-(4-Chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-isonicotinonitrile

The title compound was prepared in analogy to the synthesis of2-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-isonicotinonitrile(example 189) from 2-(piperidin-4-ylamino)-isonicotinonitriledihydrochloride (intermediate B15) and 4-chloro-3-ethoxy-benzaldehyde(intermediate E2) in a yield of 3.8 mg (6%). MS (ISP): 371.1 [M+H]⁺.

Example 1922-[1-(4-Chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-isonicotinamide

The title compound was isolated as a side-product in the synthesis of2-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-isonicotinonitrile(example 191) after purification by preparative HPLC on reversed phaseeluting with a gradient of acetonitrile/water in a yield of 15.2 mg(22%). MS (ISP): 389.5 [M+H]⁺.

Example 1932-[1-(3,5-Diisopropoxy-benzyl)-piperidin-4-ylamino]-isonicotinonitrile

The title compound was prepared in analogy to the synthesis of2-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-isonicotinonitrile(example 189) from 2-(piperidin-4-ylamino)-isonicotinonitriledihydrochloride (intermediate B15) and 3,5-diisopropoxy-benzaldehyde(intermediate E4) in a yield of 3.6 mg (5%). MS (ISP): 409.5 [M+H]⁺.

Example 1942-[1-(3,5-Diisopropoxy-benzyl)-piperidin-4-ylamino]-isonicotinamide

The title compound was isolated as a side-product in the synthesis of2-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamino]-isonicotinonitrile(example 193) after purification by preparative HPLC on reversed phaseeluting with a gradient of acetonitrile/water in a yield of 11.4 mg(15%). MS (ISP): 427.5 [M+H]⁺.

Example 1952-[1-(3,5-Diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-isonicotinonitrile

The title compound was prepared in analogy to the synthesis of2-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-isonicotinonitrile(example 189) from 2-(piperidin-4-ylamino)-isonicotinonitriledihydrochloride (intermediate B15) and3,5-diethoxy-4-fluoro-benzaldehyde (intermediate E5) in a yield of 4.3mg (6%). MS (ISP): 399.3 [M+H]⁺.

Example 1962-[1-(3,5-Diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-isonicotinamide

The title compound was isolated as a side-product in the synthesis of2-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-isonicotinonitrile(example 195) after purification by preparative HPLC on reversed phaseeluting with a gradient of acetonitrile/water in a yield of 19.1 mg(26%). MS (ISP): 417.5 [M+H]⁺.

Example 1976-[1-(4-Methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide

To a solution of 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinicacid methyl ester dihydrochloride (56.42 mg, 0.15 mmol, 1.0 equiv;intermediate B7) in ethanol (2 mL), acetic acid (72.1 mg, 1.2 mmol, 8.0equiv) and N-ethyl diisopropylamine (77.6 mg, 0.6 mmol, 4.0 equiv) wasadded 4-methoxy-3-propoxy-benzaldehyde (35.0 mg, 0.18 mmol, 1.2 equiv;intermediate E11) and the mixture stirred at 55° C. After 1 h, sodiumcyanoborohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol(0.5 mL), was added and the mixture stirred at 55° C. over night. Thesolvents were removed under reduced pressure and the residue taken up inDMAc (0.5 ml). Potassium cyanide (30.0 mg, 0.47 mmol, 3.1 equiv) and aconc. solution of NH₄OH (1 mL) was added and the reaction mixture heatedby microwave irradiation to 100° C. for 8 h. Removal of the solventunder reduced pressure and purification by preparative HPLC on reversedphase eluting with a gradient of acetonitrile/water provided 26.5 mg(38%) of the title compound. MS (ISP): 468.4 [M+H]⁺.

Example 1986-[1-(3-Isobutoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide

The title compound was prepared in analogy to the synthesis of6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide(example 197) from 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinicacid methyl ester dihydrochloride (intermediate B7) and3-isobutoxy-4-methoxy-benzaldehyde (intermediate E12) in a yield of 15.1mg (21%). MS (ISP): 482.4 [M+H]⁺.

Example 1996-[1-(4-Chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide

The title compound was prepared in analogy to the synthesis of6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide(example 197) from 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinicacid methyl ester dihydrochloride (intermediate B7) and4-chloro-3-ethoxy-benzaldehyde (intermediate E2) in a yield of 13.1 mg(19%). MS (ISP): 458.3 [M+H]⁺.

Example 2006-[1-(3,5-Diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide

The title compound was prepared in analogy to the synthesis of6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide(example 197) from 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinicacid methyl ester dihydrochloride (intermediate B7) and3,5-diethoxy-4-fluoro-benzaldehyde (intermediate E5) in a yield of 2.3mg (3%). MS (ISP): 485.3 [M+H]⁺.

Example 2016-[1-(3-Ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinicacid

To a solution of 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinicacid methyl ester dihydrochloride (56.42 mg, 0.15 mmol, 1.0 equiv;intermediate B7) in ethanol (2 mL), acetic acid (72.1 mg, 1.2 mmol, 8.0equiv) and N-ethyl diisopropylamine (77.6 mg, 0.6 mmol, 4.0 equiv) wasadded 3-ethoxy-4-hydroxy-benzaldehyde (30.0 mg, 0.18 mmol, 1.2 equiv;commercially available) and the mixture stirred at 55° C. After 1 h,sodium cyanoborohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved inethanol (0.5 mL), was added and the mixture stirred at 55° C. overnight. A solution of 10 M NaOH (0.5 mL) was added and the reactionmixture heated by microwave irradiation to 100° C. for 15 min. Removalof the solvent under reduced pressure and purification by preparativeHPLC on reversed phase eluting with a gradient of acetonitrile/waterprovided 4.3 mg (7%) of the title compound. MS (ISP): 440.3 [M+H]⁺.

Example 2026-[1-(3-Ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinicacid

The title compound was prepared in analogy to the synthesis of6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinicacid (example 201) from6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl esterdihydrochloride (intermediate B7) and 3-ethoxy-4-methoxy-benzaldehyde(commercially available) in a yield of 15.3 mg (22%). MS (ISP): 454.2[M+H]⁺.

Example 2036-[1-(4-Methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinicacid

The title compound was prepared in analogy to the synthesis of6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinicacid (example 201) from6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl esterdihydrochloride (intermediate B7) and 4-methoxy-3-propoxy-benzaldehyde(intermediate E11) in a yield of 16.4 mg (23%). MS (ISP): 468.3 [M+H]⁺.

Example 2046-[1-(3-Isobutoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinicacid

The title compound was prepared in analogy to the synthesis of6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinicacid (example 201) from6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl esterdihydrochloride (intermediate B7) and 3-isobutoxy-4-methoxy-benzaldehyde(intermediate E12) in a yield of 9.0 mg (12%). MS (ISP): 482.3 [M+H]⁺.

Example 2055-[1-(4-Chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-pyrazine-2-carboxylicacid amide

The title compound was prepared in analogy to the synthesis of6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide(example 197) from 5-(piperidin-4-ylamino)-pyrazine-2-carboxylic acidmethyl ester dihydrochloride (intermediate B14) and4-chloro-3-ethoxy-benzaldehyde (intermediate E2) in a yield of 12.1 mg(21%). MS (ISP): 390.3 [M+H]⁺.

Example 2066-[1-(4-Chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-N-(2-hydroxy-ethyl)-nicotinamide

To a mixture of6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid(65.09 mg, 0.15 mmol, 1.0 equiv; example 70) and 2-amino-ethanol (46.4mg, 0.25 mmol, 1.67 equiv; commercially available) in dry DMF (2.0 mL)and N-ethyl diisopropylamine (0.3 mL) was added HATU (68.44 mg, 0.18mmol, 1.2 equiv; commercially available) and the reaction stirred at 60°C. over night. Removal of the solvent under reduced pressure andpurification by preparative HPLC on reversed phase eluting with agradient of acetonitrile/water provided 30.1 mg (42%) of the titlecompound. MS (ISP): 477.3 [M+H]⁺.

Examples 207 to 217

According to the procedure described for the synthesis of example 207further nicotinamide derivatives have been synthesized from6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid(example 70) and the respective amine as indicated in Table 5. Theresults are compiled in Table 5 and comprise example 207 to example 217.

TABLE 5 ISP [M + H]⁺ No MW Compound Name Starting Materials found 207487.04 6-[1-(4-chloro-3,5- 6-[1-(4-chloro-3,5-diethoxy- 487.4diethoxy-benzyl)- benzyl)-piperidin-4-ylamino]- piperidin-4-ylamino]-nicotinic acid (example 70) and N-cyclobutyl- cyclobutylamine(commercially nicotinamide available) 208 490.99 ({6-[1-(4-chloro-3,5-6-[1-(4-chloro-3,5-diethoxy- 491.5 diethoxy-benzyl)-benzyl)-piperidin-4-ylamino]- piperidin-4-ylamino]- nicotinic acid(example 70) and pyridine-3-carbonyl}- amino-acetic acid (commerciallyamino)-acetic acid available) 209 491.03 6-[1-(4-chloro-3,5-6-[1-(4-chloro-3,5-diethoxy- 491.3 diethoxy-benzyl)-benzyl)-piperidin-4-ylamino]- piperidin-4-ylamino]- nicotinic acid(example 70) and N-(2-methoxy-ethyl)- 2-methoxy-ethylamine nicotinamide(commercially available) 210 503.04 {6-[1-(4-chloro-3,5-6-[1-(4-chloro-3,5-diethoxy- 503.3 diethoxy-benzyl)-benzyl)-piperidin-4-ylamino]- piperidin-4-ylamino]- nicotinic acid(example 70) and pyridin-3-yl}- morpholine (commercially morpholin-4-yl-available) methanone 211 503.04 {6-[1-(4-Chloro-3,5-6-[1-(4-chloro-3,5-diethoxy- 503.3 diethoxy-benzyl)-benzyl)-piperidin-4-ylamino]- piperidin-4-ylamino]- nicotinic acid(example 70) and pyridin-3-yl}-((R)-3- (R)-pyrrolidin-3-olhydroxy-pyrrolidin-1- (commercially available) yl)-methanone 212 507.036-[1-(4-chloro-3,5- 6-[1-(4-chloro-3,5-diethoxy- 507.4 diethoxy-benzyl)-benzyl)-piperidin-4-ylamino]- piperidin-4-ylamino]- nicotinic acid(example 70) and N-(2-hydroxy-1- 2-(2-hydroxy-ethylamino)-hydroxymethyl-ethyl)- ethanol (commercially available) nicotinamide 213514.98 6-[1-(4-chloro-3,5- 6-[1-(4-chloro-3,5-diethoxy- 515.4diethoxy-benzyl)- benzyl)-piperidin-4-ylamino]- piperidin-4-ylamino]-nicotinic acid (example 70) and N-(2,2,2-trifluoro-2,2,2-trifluoro-ethylamine ethyl)-nicotinamide (commercially available)214 518.06 N-(2-acetylamino- 6-[1-(4-chloro-3,5-diethoxy- 518.5ethyl)-6-[1-(4-chloro- benzyl)-piperidin-4-ylamino]-3,5-diethoxy-benzyl)- nicotinic acid (example 70) andpiperidin-4-ylamino]- N-(2-amino-ethyl)-acetamide nicotinamide(commercially available) 215 544.10 1-{6-[1-(4-chloro-3,5-6-[1-(4-chloro-3,5-diethoxy- 544.4 diethoxy-benzyl)-benzyl)-piperidin-4-ylamino]- piperidin-4-ylamino]- nicotinic acid(example 70) and pyridine-3-carbonyl}- piperidine-4-carboxylic acidpiperidine-4-carboxylic amide (commercially available) acid amide 216544.10 1-(4-{6-[1-(4-chloro- 6-[1-(4-chloro-3,5-diethoxy- 544.43,5-diethoxy-benzyl)- benzyl)-piperidin-4-ylamino]-piperidin-4-ylamino]- nicotinic acid (example 70) andpyridine-3-carbonyl}- 1-piperazin-1-yl-ethanone piperazin-1-yl)-(commercially available) ethanone 217 545.08 1-{6-[1-(4-chloro-3,5-6-[1-(4-chloro-3,5-diethoxy- 545.4 diethoxy-benzyl)-benzyl)-piperidin-4-ylamino]- piperidin-4-ylamino]- nicotinic acid(example 70) and pyridine-3-carbonyl}- piperidine-4-carboxylic acidpiperidine-4-carboxylic (commercially available) acid

Example 218(3-Chloro-isoquinolin-1-yl)-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-amine

Step 1: 2,6-Diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (IntermediateE22)

3,5-Diethoxy-4-iodo-benzaldehyde (14.05 g, 43.89 mmol, 1.0 equiv;intermediate E13) was dissolved under Ar in toluene (180 mL) and water(20 mL) and treated successively with 4-fluorophenyl boronic acid (12.28g, 87.78 mmol, 2.0 equiv), K₃PO₄ (50.12 g, 236.12 mmol, 5.38 equiv),tricyclohexylphosphine (2.80 g, 9.66 mmol, 0.22 equiv), andpalladium(II) acetate (1.08 g, 4.83 mmol, 0.11 equiv). The reactionmixture was heated to 100° C. for 18 h under scrupulous exclusion ofoxygen, when GC indicated the absence of starting iodo-compound. Thereaction mixture was poured on crashed ice/NH₄Cl, extracted with ethylacetate (2×200 mL) and the combined organic phases washed with a sat.solution of NaCl (2×100 mL) and water (2×100 mL). The organic phase wasdried over Na₂SO₄, concentrated by evaporation under reduced pressureand the crude material purified by silica column chromatography elutingwith a mixture of hexane/ethyl acetate (9:1). Recrystallization fromhexane/ethyl acetate provided 10.44 g (83%) of the title compound aswhite crystals. MS (EI): 288.2 [M]⁺.

Step 2:(3-Chloro-isoquinolin-1-yl)-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-amine

The title compound was prepared in analogy to the synthesis of6-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-nicotinonitrile(example 38/step 3) from(3-chloro-isoquinolin-1-yl)-piperidin-4-yl-amine dihydrochloride(intermediate B13) and 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde(intermediate E22) in a yield of 8.9 mg (11%). MS (ISP): 534.5 [M+H]⁺.

Example 2195-[1-(2,6-Diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-ylamino]-pyrazine-2-carboxylicacid methyl ester

The title compound was prepared in analogy to the synthesis of6-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-nicotinonitrile(example 38/step 3) from 5-(piperidin-4-ylamino)-pyrazine-2-carboxylicacid methyl ester dihydrochloride (intermediate B14) and2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (intermediate E22) in ayield of 5.8 mg (7%). MS (ISP): 509.4 [M+H]⁺.

The pyridine piperidine intermediates B16 to B21 were prepared followingliterature precedents or as described below.

Synthesis of Pyridine Piperidine Intermediates B16 to B21 to be Used inTable 6

Intermediate B16 (5-Methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine

Step 1: 4-(5-Methanesulfonyl-pyridin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester

To a stirred solution of 2-bromo-5-methanesulfonyl-pyridine (0.24 g, 1.0mmol, 1.0 equiv; prepared as described in EP 1298 116 A1 (PfizerProducts Inc., USA)) and 4-amino-piperidine-1-carboxylic acid tert-butylester (0.23 g, 1.1 mmol, 1.1 equiv) in acetonitrile (6.0 mL) was addedN-ethyl diisopropylamine (0.87 mL, 0.66 g, 5.0 mmol, 5.0 equiv) drop bydrop at rt and the reaction mixture heated to reflux for 19 h. Thereaction mixture was poured into crashed ice and extracted twice withethyl acetate. The combined organic layers were washed with brine andwater, dried over MgSO₄, filtered and concentrated by evaporation underreduced pressure. The crude product was purified by columnchromatography on silica eluting with a gradient ofdichloromethane/methanol to give 0.25 g (70%) of the title compound aslight brown oil. MS (ISP): 356.1 [M+H]⁺.

Step 2: (5-Methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine

To a stirred solution of4-(5-methanesulfonyl-pyridin-2-ylamino)-piperidine-1-carboxylic acidtert-butyl ester (1.00 g, 2.8 mmol, 1.0 equiv) in ethanol (18 mL) wasadded 4 M HCl in dioxane (3.52 mL, 14.1 mmol, 5.0 equiv) drop by dropand the reaction mixture stirred at 50° C. for 2 h. It was then cooleddown to rt, poured into ice water and the pH adjusted to 9-10 byaddition of a sat. solution of potassium carbonate. The solution wasextracted six times with a mixture of dichloromethane/isopropanol (4:1).The combined organic layers were concentrated by evaporation underreduced pressure and the crude product was purified by crystallizationfrom heptane to give 0.53 g (74%) of the title compound as colorlesssolid. MS (ISP): 256.2 [M+H]⁺.

Intermediate B17 2-Chloro-6-(piperidin-4-ylamino)-isonicotinic acidmethyl ester

Step 1:2-(1-tert-Butoxycarbonyl-piperidin-4-ylamino)-6-chloro-isonicotinic acidmethyl ester

A stirred suspension of 2,6-dichloro-isonicotinic acid methyl ester(4.52 g, 21.9 mmol 1.0 equiv), 4-amino-piperidine-1-carboxylic acidtert-butyl ester (4.39 g, 21.9 mmol, 1.0 equiv), palladium(II) acetate(0.50 g, 2.2 mmol, 0.1 equiv) andrac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (1.39 g, 2.2 mmol,0.1 equiv) in toluene (150 mL) was treated at rt with caesium carbonate(9.39 g, 28.5 mmol, 1.3 equiv) and then warmed to 80° C. After 6 h, thereaction mixture was poured into crashed ice and extracted twice withethyl acetate. The combined organic layers were washed with brine andwater, dried over MgSO₄, filtered and concentrated by evaporation underreduced pressure. The crude product was purified by columnchromatography on silica eluting with a gradient ofdichloromethane/methanol to give 5.40 g (67%) of the title compound as alight yellow solid. MS (ISP): 370.1 [M+H]⁺.

Step 2: 2-Chloro-6-(piperidin-4-ylamino)-isonicotinic acid methyl ester

The title compound was prepared in analogy to the synthesis of(5-methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine (intermediateB16/step 2) from2-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-6-chloro-isonicotinic acidmethyl ester by cleavage of the BOC group with 4 M HCl in dioxane andethanol at rt. MS (ISP): 270.1 [M+H]⁺.

Intermediate B18 [6-(Piperidin-4-ylamino)-pyridin-3-yloxy]-acetonitrile

Step 1: 4-(5-Benzyloxy-pyridin-2-ylamino)-piperidine-1-carboxylic acidtert-butyl ester

A stirred suspension of 5-benzyloxy-2-chloro-pyridine (12.4 g, 56.4mmol, 1.0 equiv; prepared as described in WO 9728 128 A1 (Zeneca Ltd.,UK)), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (11.31 g,56.4 mmol, 1.0 equiv), palladium(II) acetate (0.51 g, 2.3 mmol, 0.04equiv) and rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (1.44 g,2.3 mmol, 0.04 equiv) in toluene (250 mL) was treated at rt withKOtert-Bu (6.71 g, 67.7 mmol, 1.2 equiv) and subsequently warmed to 70°C. After 7 h, the reaction mixture was poured into crashed ice andfiltered over dicalite and extracted twice with toluene. The combinedorganic layers were dried over MgSO₄, filtered and concentrated byevaporation under reduced pressure. The crude product was purified bycolumn chromatography on silica eluting with a gradient ofdichloromethane/methanol to give 18.73 g (87%) of the title compound asa light yellow solid. MS (ISP): 384.1 [M+H]⁺.

Step 2: 4-(5-Hydroxy-pyridin-2-ylamino)-piperidine-1-carboxylic acidtert-butyl ester

To a solution of4-(5-benzyloxy-pyridin-2-ylamino)-piperidine-1-carboxylic acidtert-butyl ester (18.2 g, 47.5 mmol, 1.0 equiv) in methanol (200 mL) wasadded 10% Pd on activated carbon (2.53 g, 2.38 mmol 0.05 equiv) under anatmosphere of Ar. The reaction vessel was twice evacuated and ventilatedwith hydrogen gas and the well stirred reaction mixture was subsequentlyhydrogenated at rt and 1 bar H₂ for 3 h. After filtration over dicalitethe crude reaction mixture was concentrated by evaporation under reducedpressure and purified by column chromatography on silica eluting with agradient of dichloromethane/methanol to give 10.50 g (75%) of the titlecompound as a light yellow solid. MS (ISP): 294.2 [M+H]⁺.

Step 3:4-(5-tert-Butoxycarbonyloxy-pyridin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester

To a mechanically stirred suspension of4-(5-hydroxy-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butylester (9.86 g, 33.6 mmol, 1.0 equiv) and sodium bicarbonate (28.52 g,33.6 mmol, 1.0 equiv) in a mixture of water and dioxane (1:1) (500 mL)at rt was added di-tert-butyl-dicarbonate (37.43 g, 168 mmol, 5.0 equiv)in several small portions and the mixture stirred for 24 h. Theheterogeneous reaction mixture was subsequently poured into cold water,carefully acidified with 25% HCl to adjust the pH to around 3 andextracted twice with ethyl acetate. The combined organic layers werewashed with brine and water, dried over MgSO₄, filtered and concentratedby evaporation under reduced pressure. The crude product was purified bycolumn chromatography on silica eluting with a gradient ofdichloromethane/methanol to give 13.64 g (100%) of the title compound asa light yellow solid. MS (ISP): 394.2 [M+H]⁺.

Step 4:4-[tert-Butoxycarbonyl-(5-tert-butoxycarbonyloxy-pyridin-2-yl)-amino]-piperidine-1-carboxylicacid tert-butyl ester

To a well stirred suspension of4-(5-tert-butoxycarbonyloxy-pyridin-2-ylamino)-piperidine-1-carboxylicacid tert-butyl ester (9.58 g, 24.3 mmol, 1.0 equiv) andN,N-dimethyl-pyridin-4-yl-amine (1.52 g, 12.2 mmol, 0.5 equiv) inacetonitrile (200 mL) at rt was added di-tert-butyl-dicarbonate (23.86g, 107 mmol, 4.4 equiv) in several small portions and stirring continuedfor 44 h. The reaction mixture was then poured into cold water andextracted twice with ethyl acetate. The combined organic layers werewashed with brine and water, dried over MgSO₄, filtered and concentratedby evaporation under reduced pressure. The crude product was purified bycolumn chromatography on silica eluting with a gradient of heptane/ethylacetate to give 6.17 g (51%) of the title compound as yellow solid. MS(ISP): 494.3 [M+H]⁺.

Step 5:4-[tert-Butoxycarbonyl-(5-hydroxy-pyridin-2-yl)-amino]-piperidine-1-carboxylicacid tert-butyl ester

To a solution of4-[tert-butoxycarbonyl-(5-tert-butoxycarbonyloxy-pyridin-2-yl)-amino]-piperidine-1-carboxylicacid tert-butyl ester (6.75 g, 13.7 mmol, 1.0 equiv) in a mixture ofTHF/methanol (1:1) (100 mL) at 3° C. was added drop by drop a solutionof 1 M LiOH (34.2 mL, 34.5 mmol, 2.5 equiv) and after the addition wascompleted the mixture warmed up to rt. After 18 h, the reaction mixturewas poured into cold water and extracted three times withdichloromethane. The combined organic layers were washed with brine andwater, dried over MgSO₄, filtered and concentrated by evaporation underreduced pressure. The crude product was purified by columnchromatography on silica eluting with a gradient ofdichloromethane/methanol to give 4.31 g (80%) of the title compound asorange foam. MS (ISP): =394.1 [M+H]⁻.

Step 6:4-[tert-Butoxycarbonyl-(5-cyanomethoxy-pyridin-2-yl)-amino]-piperidine-1-carboxylicacid tert-butyl ester

To a stirred solution of4-[tert-butoxycarbonyl-(5-hydroxy-pyridin-2-yl)-amino]-piperidine-1-carboxylicacid tert-butyl ester (0.79 g, 2.0 mmol, 1.0 equiv) in acetonitrile (20mL) was added potassium carbonate (0.84 g, 6.0 mmol, 3.0 equiv),followed by bromoacetonitrile (0.21 mL, 0.37 g, 3.0 mmol, 1.5 equiv).After stirring at rt for 16 h, the reaction mixture was poured into icewater and extracted twice with ethyl acetate. The combined organiclayers were washed with water, dried over MgSO₄, filtered andconcentrated by evaporation under reduced pressure. The crude productwas purified by column chromatography on silica eluting with a gradientof dichloromethane/methanol to give 0.93 g (100%) of the title compoundas light brown oil. MS (ISP): 433.3 [M+H]⁺.

Step 7: [6-(Piperidin-4-ylamino)-pyridin-3-yloxy]-acetonitrile

To a stirred solution of4-[tert-butoxycarbonyl-(5-cyanomethoxy-pyridin-2-yl)-amino]-piperidine-1-carboxylicacid tert-butyl ester (0.90 g, 2.1 mmol, 1.0 equiv) in dichloromethane(15 mL) was added 90% trifluoroacetic acid (1.69 mL, 2.37 g, 19 mmol,9.0 equiv) drop by drop and the reaction mixture stirred at rt for 16 h.It was then poured into ice water and the pH adjusted to 9-10 byaddition of a sat. solution of potassium carbonate. The solution wasextracted three times with a mixture of dichloromethane/isopropanol(4:1). The combined organic layers were concentrated by evaporationunder reduced pressure to give 0.15 g (30%) of the title compound asyellow oil. MS (ISP): 233.0 [M+H]⁻.

Intermediate B19rac-3-[6-(Piperidin-4-ylamino)-pyridin-3-yloxy]-propane-1,2-diol

Step 1:rac-4-{tert-Butoxycarbonyl-[5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-pyridin-2-yl]-amino}-piperidine-1-carboxylicacid tert-butyl ester

To a stirred solution of4-[tert-butoxycarbonyl-(5-hydroxy-pyridin-2-yl)-amino]-piperidine-1-carboxylicacid tert-butyl ester (intermediate B18/step 5) (0.79 g, 2.0 mmol, 1.0equiv) in DMF (20 mL) was added potassium carbonate (0.62 g, 4.4 mmol,2.2 equiv), followed by rac-toluene-4-sulfonic acid2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (0.65 g, 2.2 mmol, 1.1equiv; commercially available). The reaction mixture was heated to 100°C. for 16 h and then poured into ice water and extracted twice withether. The combined organic layers were washed with water, dried overMgSO₄, filtered and concentrated by evaporation under reduced pressure.The crude product was purified by column chromatography on silicaeluting with a gradient of dichloromethane/methanol to give 0.99 g (97%)of the title compound as light yellow oil. MS (ISP): 508.3 [M+H]⁺.

Step 2: rac-3-[6-(Piperidin-4-ylamino)-pyridin-3-yloxy]-propane-1,2-diol

The title compound was prepared in analogy to the procedure describedfor (5-methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine (intermediateB16/step 2) fromrac-4-{tert-butoxycarbonyl-[5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-pyridin-2-yl]-amino}-piperidine-1-carboxylicacid tert-butyl ester by cleavage of both the BOC and the isopropylidenegroup with 4 M HCl in dioxane and ethanol at rt followed by ion exchangechromatography on Q-Sepharose Fast Flow. MS (ISP): 268.2 [M+H]⁺.

Intermediate B20 3-[6-(Piperidin-4-ylamino)-pyridin-3-yloxy]-propan-1-ol

The title compound was prepared in analogy to the procedure describedforrac-4-{tert-butoxycarbonyl-[5-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-pyridin-2-yl]-amino}-piperidine-1-carboxylicacid tert-butyl ester (intermediate B19/step 1) from4-[tert-butoxycarbonyl-(5-hydroxy-pyridin-2-yl)-amino]-piperidine-1-carboxylicacid tert-butyl ester (intermediate B18 step 5) by reaction withrac-2-(3-bromopropoxy)-tetrahydro-2H-pyran (commercially available) andpotassium carbonate in DMF at rt, followed by BOC and THP cleavage with4 M HCl in dioxane and ethanol at 70° C. in analogy to the synthesis of(5-methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine (intermediateB16/step 2). MS (ISP): 252.1 [M+H]⁻.

Intermediate B21 Methanesulfonic acid6-(piperidin-4-ylamino)-pyridin-3-yl ester

Step 1:4-[tert-Butoxycarbonyl-(5-methanesulfonyloxy-pyridin-2-yl)-amino]-piperidine-1-carboxylicacid tert-butyl ester

To a stirred solution of4-[tert-butoxycarbonyl-(5-hydroxy-pyridin-2-yl)-amino]-piperidine-1-carboxylicacid tert-butyl ester (0.60 g, 1.5 mmol, 1.0 equiv; intermediateB18/step 5) and potassium carbonate (0.64 g, 4.6 mmol, 3.1 equiv) in DMF(15 mL) was added slowly methanesulfonyl chloride (0.18 mL, 0.27 g, 2.3mmol, 1.5 equiv). After stirring at rt for 20 h, the reaction mixturewas poured into ice water and extracted twice with diethyl ether. Thecombined organic layers were washed with water, dried over MgSO₄,filtered and concentrated by evaporation under reduced pressure. Thecrude product was purified by column chromatography on silica elutingwith a gradient of dichloromethane/methanol to give 0.39 g (55%) of thetitle compound as light brown solid. MS (ISP): 472.2 [M+H]⁺.

Step 2: Methanesulfonic acid 6-(piperidin-4-ylamino)-pyridin-3-yl ester

The title compound was prepared in analogy to the procedure describedfor (5-methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine (intermediateB16/step 2) from4-[tert-butoxycarbonyl-(5-methanesulfonyloxy-pyridin-2-yl)-amino]-piperidine-1-carboxylicacid tert-butyl ester by cleavage of the BOC group with 4 M HCl indioxane and ethanol at 70° C. MS (ISP): 272.1 [M+H]⁺.

Example 220[1-(3,5-Diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-(5-methanesulfonyl-pyridin-2-yl)-amine

To a solution of (5-methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine(0.12 g, 0.5 mmol, 1.0 equiv; intermediate B16) and3,5-diethoxy-4-fluoro-benzaldehyde (0.11 g, 0.5 mmol, 1.0 equiv;intermediate E5) in ethanol (5 mL) under an atmosphere of Ar was addedN-ethyl diisopropylamine (0.19 mL, 0.15 g, 1.2 mmol, 2.3 equiv) andglacial acetic acid (0.05 mL, 0.06 g, 1.0 mmol, 2.0 equiv) and themixture heated to 50° C. for 2 h. After cooling down to 35° C., sodiumcyanoborohydride (0.16 g, 2.5 mmol, 5.1 equiv) was added and thereaction mixture heated again to 50° C. for 1.5 h. It was then pouredinto crashed ice, the pH of the water phase adjusted to ˜10 by additionof a sat. solution of sodium carbonate and the mixture extracted twicewith dichloromethane. The combined organic phases were washed withwater, dried over MgSO₄, filtered and concentrated by evaporation underreduced pressure. The crude product was purified by columnchromatography on silica eluting with a gradient ofdichloromethane/methanol to give 0.16 g (71%) of the title compound ascolorless foam. MS (ISP): 452.1 [M+H]⁺.

Examples 221 to 231

According to the procedure described for the synthesis of example 220further pyridine derivatives have been synthesized from(5-methanesulfonyl-pyridin-2-yl)-piperidin-4-yl-amine (intermediateB16), 2-chloro-6-(piperidin-4-ylamino)-isonicotinic acid methyl ester(intermediate B17),[6-(piperidin-4-ylamino)-pyridin-3-yloxy]-acetonitrile (intermediateB18),rac-3-[6-(piperidin-4-ylamino)-pyridin-3-yloxy]-propane-1,2-diol_(intermediateB19), 3-[6-(piperidin-4-ylamino)-pyridin-3-yloxy]-propan-1-ol(intermediate B20) and methanesulfonic acid6-(piperidin-4-ylamino)-pyridin-3-yl ester (intermediate B21) and therespective benzaldehyde intermediates as indicated in Table 6. Theresults are compiled in Table 6 and comprise example 221 to example 231.

TABLE 6 ISP [M + H]⁺ No. MW Compound Name Starting Materials found 221468.02 [1-(4-chloro-3,5- (5-methanesulfonyl-pyridin- [M + H]⁺diethoxy-benzyl)- 2-yl)-piperidin-4-yl-amine 468.1 piperidin-4-yl]-(5-(intermediate B16) and 4- methanesulfonyl- chloro-3,5-diethoxy-pyridin-2-yl)-amine benzaldehyde (intermediate E6) 222 527.66[1-(2,6-diethoxy-4′- (5-methanesulfonyl-pyridin- [M + H]⁺fluoro-biphenyl-4- 2-yl)-piperidin-4-yl-amine 528.2ylmethyl)-piperidin-4- (intermediate B16) and 2,6-yl]-(5-methanesulfonyl- diethoxy-4′-fluoro-biphenyl- pyridin-2-yl)-amine4-carbaldehyde (intermediate E22) 223 465.95 2-chloro-6-[1-(3,5-2-chloro-6-(piperidin-4- [M + H]⁺ diethoxy-4-fluoro-ylamino)-isonicotinic acid 466.2 benzyl)-piperidin-4- methyl ester(intermediate ylamino]-isonicotinic acid B17) and 3,5-diethoxy-4- methylester fluoro-benzaldehyde (intermediate E5) 224 482.412-chloro-6-[1-(4-chloro- 2-chloro-6-(piperidin-4- [M + H]⁺3,5-diethoxy-benzyl)- ylamino)-isonicotinic acid 482.2piperidin-4-ylamino]- methyl ester (intermediate isonicotinic acidmethyl B17) and 4-chloro-3,5- ester diethoxy-benzaldehyde (intermediateE6) 225 542.05 2-chloro-6-[1-(2,6- 2-chloro-6-(piperidin-4- [M + H]⁺diethoxy-4′-fluoro- ylamino)-isonicotinic acid 542.2biphenyl-4-ylmethyl)- methyl ester (intermediate piperidin-4-ylamino]-B17) and 2,6-diethoxy-4′- isonicotinic acid methyl fluoro-biphenyl-4-ester carbaldehyde (intermediate E22) 226 504.60 {6-[1-(2,6-diethoxy-4′-[6-(piperidin-4-ylamino)- [M + H]⁺ fluoro-biphenyl-4-pyridin-3-yloxy]-acetonitrile 505.3 ylmethyl)-piperidin-4- (intermediateB18) and 2,6- ylamino]-pyridin-3- diethoxy-4′-fluoro-biphenyl-yloxy}-acetonitrile 4-carbaldehyde (intermediate E22) 227 480.00rac-3-{6-[1-(4-chloro- rac-3-[6-(piperidin-4- [M + H]⁺3,5-diethoxy-benzyl)- ylamino)-pyridin-3-yloxy]- 480.1piperidin-4-ylamino]- propane-1,2-diol pyridin-3-yloxy}- (intermediateB19) and 4- propane-1,2-diol chloro-3,5-diethoxy- benzaldehyde(intermediate E6) 228 539.64 rac-3-{6-[1-(2,6- rac-3-[6-(piperidin-4-[M + H]⁺ diethoxy-4′-fluoro- ylamino)-pyridin-3-yloxy]- 540.3biphenyl-4-ylmethyl)- propane-1,2-diol piperidin-4-ylamino]-(intermediate B19) and 2,6- pyridin-3-yloxy}-diethoxy-4′-fluoro-biphenyl- propane-1,2-diol 4-carbaldehyde(intermediate E22) 229 523.65 3-{6-[1-(2,6-diethoxy-4′-3-[6-(piperidin-4-ylamino)- [M + H]⁺ fluoro-biphenyl-4-pyridin-3-yloxy]-propan-1-ol 524.2 ylmethyl)-piperidin-4- (intermediateB20) and 2,6- ylamino]-pyridin-3- diethoxy-4′-fluoro-biphenyl-yloxy}-propan-1-ol 4-carbaldehyde (intermediate E22) 230 464.003-{6-[1-(4-chloro-3,5- 3-[6-(piperidin-4-ylamino)- [M + H]⁺diethoxy-benzyl)- pyridin-3-yloxy]-propan-1-ol 464.2piperidin-4-ylamino]- (intermediate B20) and 4- pyridin-3-yloxy}-propan-chloro-3,5-diethoxy- 1-ol benzaldehyde (intermediate E6) 231 543.66methanesulfonic acid 6- methanesulfonic acid 6- [M + H]⁺[1-(2,6-diethoxy-4′- (piperidin-4-ylamino)- 544.3 fluoro-biphenyl-4-pyridin-3-yl ester ylmethyl)-piperidin-4- (intermediate B21) and 2,6-ylamino]-pyridin-3-yl diethoxy-4′-fluoro-biphenyl- ester 4-carbaldehyde(intermediate E22)

Example 2322-Chloro-6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-isonicotinicacid

To a stirred solution of2-chloro-6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-isonicotinicacid methyl ester (0.17 g, 0.35 mmol, 1.0 equiv; example 224) inTHF/methanol (2:1) (15 mL) was added a solution of 1 M LiOH (0.87 mL,0.87 mmol. 2.5 equiv) drop by drop. After 16 h, the reaction mixture waspoured into ice water, the pH of the water phase adjusted to 3-4 withdiluted HCl and the mixture extracted twice with dichloromethane. Theorganic phases were washed with water, dried over MgSO₄, filtered andconcentrated by evaporation under reduced pressure. The crude productwas purified by column chromatography on silica eluting with a gradientof dichloromethane/methanol to give 0.12 g (73%) of the title compoundas colorless solid. MS (ISP): 468.3 [M+H]⁺.

Example 2332-Chloro-6-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-ylamino]-isonicotinicacid

The title compound was prepared in analogy to the procedure describedfor2-chloro-6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-isonicotinicacid (example 232) from2-chloro-6-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-ylamino]-isonicotinicacid methyl ester (example 225) and obtained as colorless solid. MS(ISN): 526.1 [M−H].

Example A

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula I 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mgMagnesium stearate  1.5 mg  4.5 mg (Kernel Weight) 120.0 mg  350.0 mgFilm Coat: Hydroxypropyl methyl cellulose  3.5 mg  7.0 mg Polyethyleneglycol 6000  0.8 mg  1.6 mg Talc  1.3 mg  2.6 mg Iron oxide (yellow) 0.8 mg  1.6 mg Titanium dioxide  0.8 mg  1.6 mg

The active ingredient is sieved and mixed with microcrystallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidone in water. The granulate is mixed with sodium starchglycolate and magnesium stearate and compressed to yield kernels of 120or 350 mg respectively. The kernels are lacquered with an aqueoussolution/suspension of the above mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula I 25.0 mg Lactose 150.0 mg Maize starch 20.0 mg Talc  5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C

Injection solutions can have the following composition:

Compound of formula I 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Sodiumcarbonate to obtain a final pH of 7 Water for injection solutions ad 1.0ml

Example D

Soft gelatin capsules containing the following ingredients can bemanufactured in a conventional manner:

Capsule contents Compound of formula I 5.0 mg Yellow wax 8.0 mgHydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant oils 34.0mg Soya bean oil 110.0 mg Weight of capsule contents 165.0 mg Gelatincapsule Gelatin 75.0 mg Glycerol 85% 32.0 mg Karion 83 8.0 mg (drymatter) Titanium dioxide 0.4 mg Iron oxide yellow 1.1 mg

The active ingredient is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

Example E

Sachets containing the following ingredients can be manufactured in aconventional manner:

Compound of formula I 50.0 mg Lactose, fine powder 1015.0 mg Microcrystalline cellulose (AVICEL PH 102) 1400.0 mg  Sodiumcarboxymethyl cellulose 14.0 mg Polyvinylpyrrolidone K 30 10.0 mgMagnesium stearate 10.0 mg Flavoring additives  1.0 mg

The active ingredient is mixed with lactose, microcrystalline celluloseand sodium carboxymethyl cellulose and granulated with a mixture ofpolyvinylpyrrolidone in water. The granulate is mixed with magnesiumstearate and the flavouring additives and filled into sachets.

It is to be understood that the invention is not limited to theparticular embodiments of the invention described above, as variationsof the particular embodiments may be made and still fall within thescope of the appended claims.

1. A compound of formula (I):

wherein A is —O— or —NH—; R¹ is selected from the group consisting ofhydrogen, C₁₋₇-alkoxy and halogen; R² is selected from the groupconsisting of C₂₋₇-alkyl, C₂₋₇-alkenyl, halogen-C₁₋₇-alkyl,C₁₋₇-alkoxy-C₁₋₇-alkyl, and benzyl; R³ is selected from the groupconsisting of hydrogen, C₁₋₇-alkyl, hydroxy, C₁₋₇-alkoxy,C₂₋₇-alkenyloxy, hydroxy-C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkoxy,—O—C₃₋₇-cycloalkyl, halogen, halogen-C₁₋₇-alkyl, halogen-C₁₋₇-alkoxy,—C(O)OR⁶, wherein R⁶ is C₁₋₇-alkyl, amino, pyrrolyl, unsubstitutedphenyl or phenyl substituted by one to three groups independentlyselected from C₁₋₇-alkyl, halogen and C₁₋₇-alkoxy; R⁴ is selected fromthe group consisting of hydrogen, hydroxy, C₁₋₇-alkoxy, amino, nitro,hydroxy-C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkoxy, and —O-benzyl; R⁵ isselected from the group consisting of hydrogen, halogen and C₁₋₇-alkoxy;G is

wherein R¹² is selected from the group consisting of hydrogen,C₁₋₇-alkyl, halogen and amino; R¹³ is selected from the group consistingof hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl, cyano, nitro,phenyl, tetrazolyl, benzoimidazolyl, —COOR²⁹, wherein R²⁹ is hydrogen orC₁₋₇-alkyl, hydroxy-C₁₋₇-alkoxy, cyano-C₁₋₇-alkoxy, —CONHR³⁰, whereinR³⁰ is selected from the group consisting of hydrogen, C₁₋₇-alkyl,C₃₋₇-cycloalkyl, hydroxy-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl,halogen-C₁₋₇-alkyl, carboxy-C₁₋₇-alkyl, —(CH₂)_(n)—NH—C(O)—R³¹, whereinn is 1 or 2 and R³¹ is C₁₋₇-alkyl, —S(O)₂—R³³, wherein R³³ isC₁₋₇-alkyl, —O—S(O)₂—R³⁴, wherein R³⁴ is C₁₋₇-alkyl, and—CO-heterocyclyl, wherein heterocyclyl is a ring selected frompyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, said ring beingunsubstituted or substituted by a group selected from hydroxy, carboxy,carbamoyl and C₁₋₇-alkanoyl; R¹⁴ is selected from the group consistingof hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkyl, cyano,carbamoyl, —COOR³⁵, wherein R^(3s) is hydrogen or C₁₋₇-alkyl, halogenand halogen-C₁₋₇-alkyl; R¹⁵ is selected from the group consisting ofhydrogen, cyano, halogen and halogen-C₁₋₇-alkyl; and pharmaceuticallyacceptable salts thereof.
 2. The compound according to claim 1, whereinA is O.
 3. The compound according to claim 1, wherein R¹ is hydrogen. 4.The compound according to claim 1, wherein R² is selected from the groupconsisting of C₂₋₇-alkyl, C₂₋₇-alkenyl and halogen-C₁₋₇-alkyl.
 5. Thecompound according to claim 1, wherein R² is selected from the groupconsisting of ethyl, propyl, isopropyl, allyl, 2-fluoroethyl, butyl andisobutyl.
 6. The compound according to claim 1, wherein R³ is selectedfrom the group consisting of hydrogen, C₁₋₇-alkyl, hydroxy, C₁₋₇-alkoxy,halogen, halogen-C₁₋₇-alkoxy, —C(O)OR⁶, wherein R⁶ is C₁₋₇-alkyl, aminoand pyrrolyl.
 7. The compound according to claim 1, wherein R³ isselected from the group consisting of hydrogen, C₁₋₇-alkoxy and halogen.8. The compound according to claim 1, wherein R³ is halogen.
 9. Thecompound according to claim 1, wherein R⁴ is selected from the groupconsisting of hydrogen, hydroxy, C₁₋₇-alkoxy andC₁₋₇-alkoxy-C₁₋₇-alkoxy.
 10. The compound according to claim 1, whereinR⁵ is hydrogen.
 11. The compound according to claim 1, wherein R¹², R¹⁴and R¹⁵ are hydrogen; and R¹³ is selected from the group consisting ofC₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl, cyano, nitro, phenyl,tetrazolyl, benzoimidazolyl, —COOR²⁹, wherein R²⁹ is hydrogen orC₁₋₇-alkyl, —CONHR³⁰, wherein R³⁰ is selected from the group consistingof hydrogen, C₁₋₇-alkyl, C₃₋₇-cycloalkyl, hydroxy-C₁₋₇-alkyl,C₁₋₇-alkoxy-C₁₋₇-alkyl, halogen-C₁₋₇-alkyl, carboxy-C₁₋₇-alkyl,—(CH₂)_(n)—NH—C(O)—R³¹, wherein n is 1 or 2 and R³¹ is C₁₋₇-alkyl, and—CO-heterocyclyl, wherein heterocyclyl is a ring selected frompyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, said ring beingunsubstituted or substituted by a group selected from hydroxy, carboxy,carbamoyl and C₁₋₇-alkanoyl.
 12. The compound according to claim 1,having the formula

wherein A is —O— or —NH—; R¹ is selected from the group consisting ofhydrogen, C₁₋₇-alkoxy and halogen; R² is selected from the groupconsisting of C₂₋₇-alkyl, C₂₋₇-alkenyl, halogen-C₁₋₇-alkyl,C₁₋₇-alkoxy-C₁₋₇-alkyl, and benzyl; R³ is selected from the groupconsisting of hydrogen, C₁₋₇-alkyl, hydroxy, C₁₋₇-alkoxy,C₂₋₇-alkenyloxy, hydroxy-C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkoxy,—O—C₃₋₇-cycloalkyl, halogen, halogen-C₁₋₇-alkyl, halogen-C₁₋₇-alkoxy,—C(O)OR⁶, wherein R⁶ is C₁₋₇-alkyl, amino and pyrrolyl; R⁴ is selectedfrom the group consisting of hydrogen, hydroxy, C₁₋₇-alkoxy, amino,nitro, hydroxy-C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkoxy, and —O-benzyl; R⁵is selected from the group consisting of hydrogen, halogen andC₁₋₇-alkoxy, G is

wherein R¹² is selected from the group consisting of hydrogen,C₁₋₇-alkyl, halogen and amino; R¹³ is selected from the group consistingof hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl, cyano, nitro,phenyl, tetrazolyl, benzoimidazolyl, —COOR²⁹, wherein R²⁹ is hydrogen orC₁₋₇-alkyl, —CONHR³⁰, wherein R³⁰ is selected from the group consistingof hydrogen, C₁₋₇-alkyl, C₃₋₇-cycloalkyl, hydroxy-C₁₋₇-alkyl,C₁₋₇-alkoxy-C₁₋₇-alkyl, halogen-C₁₋₇-alkyl, carboxy-C₁₋₇-alkyl,—(CH₂)_(n)—NH—C(O)—R³¹, wherein n is 1 or 2 and R³¹ is C₁₋₇-alkyl, and—CO-heterocyclyl, wherein heterocyclyl is a ring selected frompyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, said ring beingunsubstituted or substituted by a group selected from hydroxy, carboxy,carbamoyl and C₁₋₇-alkanoyl; R¹⁴ is selected from the group consistingof hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkyl, cyano,carbamoyl, halogen and halogen-C₁₋₇-alkyl; R¹⁵ is selected from thegroup consisting of hydrogen, cyano, halogen and halogen-C₁₋₇-alkyl; andpharmaceutically acceptable salts thereof.
 13. The compound according toclaim 1, selected from the group consisting of[5-(1H-benzoimidazol-2-yl)-pyridin-2-yl]-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine,6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-nicotinonitrile,[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,(6-chloro-pyridin-2-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine,6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-nicotinic acidethyl ester,6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-nicotinic acidmethyl ester,[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(5-nitro-pyridin-2-yl)-amine,(5-bromo-pyridin-2-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine,[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(6-methyl-5-nitro-pyridin-2-yl)-amine,N⁶-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-3-nitro-pyridine-2,6-diamine,2-chloro-6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-isonicotinicacid methyl ester,2-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-6-methyl-5-phenyl-nicotinonitrile,2-chloro-6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-5-fluoro-nicotinonitrile,{2-chloro-6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-pyridin-4-yl}-methanol,6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-nicotinic acidmethyl ester,[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(3-trifluoromethyl-pyridin-2-yl)-amine,[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(6-methyl-5-nitro-pyridin-2-yl)-amine,N⁶-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-3-nitro-pyridine-2,6-diamine,[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(6-chloro-4-methoxymethyl-pyridin-2-yl)-amine,2-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-6-methyl-nicotinonitrile,6-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-nicotinonitrile,6-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-nicotinonitrile,6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-nicotinonitrile,6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-nicotinonitrile,6-[1-(3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinonitrile,6-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamino]-nicotinonitrile,6-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-nicotinonitrile,6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinonitrile,6-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinonitrile,6-[1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinonitrile,6-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-ylamino]-nicotinonitrile,6-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-nicotinamide,6-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-nicotinamide,6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-nicotinamide,6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,6-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,6-[1-(3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,6-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,6-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-nicotinamide,6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,6-[1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,6-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-ylamino]-nicotinamide,6-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-nicotinic acid,6-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-nicotinic acid,6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid,6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-nicotinic acid,6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid,6-[1-(3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid,6-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid,6-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-nicotinic acid,6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid,[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-[5-(1H-tetrazol-5-yl)-pyridin-2-yl]-amine,[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-[5-(1H-tetrazol-5-yl)-pyridin-2-yl]-amine,[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-[5-(1H-tetrazol-5-yl)-pyridin-2-]yl-amine,[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-[5-(1H-tetrazol-5-yl)-pyridin-2-yl]-amine,[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-[5-(1H-tetrazol-5-yl)-pyridin-2-yl]-amine,[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,[1-(3,5-diethoxy-4-iodo-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,[1-(3-ethoxy-4-iodo-5-methoxymethoxy-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine,6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinicacid methyl ester,6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinicacid methyl ester,6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinicacid methyl ester,6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinicacid methyl ester,6-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinicacid methyl ester,2-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-isonicotinonitrile,2-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-isonicotinamide,2-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-isonicotinonitrile,2-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-isonicotinamide,2-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamino]-isonicotinonitrile,2-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamino]-isonicotinamide,2-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-isonicotinonitrile,2-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-isonicotinamide,6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide,6-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide,6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide,6-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinamide,6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinicacid,6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinicacid,6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinicacid,6-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinicacid,6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-N-(2-hydroxy-ethyl)-nicotinamide,6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-N-cyclobutyl-nicotinamide,({6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridine-3-carbonyl}-amino)-aceticacid,6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-N-(2-methoxy-ethyl)-nicotinamide,{6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridin-3-yl}-morpholin-4-yl-methanone,{6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridin-3-yl}-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone,6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-N-(2-hydroxy-1-hydroxymethyl-ethyl)-nicotinamide,6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-N-(2,2,2-trifluoro-ethyl)-nicotinamide,N-(2-acetylamino-ethyl)-6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,1-{6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridine-3-carbonyl}-piperidine-4-carboxylicacid amide, 1-(4-{6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridine-3-carbonyl}-piperazin-1-yl)-ethanone,1-{6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridine-3-carbonyl}-piperidine-4-carboxylicacid, and pharmaceutically acceptable salts thereof.
 14. The compoundaccording to claim 1, selected from the group consisting of[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-(5-methanesulfonyl-pyridin-2-yl)-amine,[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(5-methanesulfonyl-pyridin-2-yl)-amine,[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-yl]-(5-methanesulfonyl-pyridin-2-yl)-amine,2-chloro-6-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-isonicotinicacid methyl ester,2-chloro-6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-isonicotinicacid methyl ester,2-chloro-6-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-ylamino]-isonicotinicacid methyl ester,{6-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-ylamino]-pyridin-3-yloxy}-acetonitrile,3-{6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridin-3-yloxy}-propane-1,2-diol,3-{6-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-ylamino]-pyridin-3-yloxy}-propane-1,2-diol,3-{6-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-ylamino]-pyridin-3-yloxy}-propane-1,2-diol,3-{6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridin-3-yloxy}-propan-1-ol,methanesulfonic acid6-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-ylamino]-pyridin-3-ylester,2-chloro-6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-isonicotinicacid,2-chloro-6-[1-(2,6-diethoxy-4′-fluoro-biphenyl-4-ylmethyl)-piperidin-4-ylamino]-isonicotinicacid, or pharmaceutically acceptable salts thereof.
 15. The compoundaccording to claim 1, selected from the group consisting of6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinamide,6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid,6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid,[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-[5-(1H-tetrazol-5-yl)-pyridin-2-yl]-amine,({6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridine-3-carbonyl}-amino)-aceticacid,{6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridin-3-yl}-morpholin-4-yl-methanone,1-{6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyridine-3-carbonyl}-piperidine-4-carboxylicacid, or pharmaceutically acceptable salts thereof
 16. A pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundaccording to claim 1 as well as a pharmaceutically acceptable carrierand/or adjuvant.